Epigenetics is the study of heritable changes in gene function that do
not involve changes in the
DNA sequence. The Greek prefix epi-
(ἐπι- "over, outside of, around") in epigenetics implies features
that are "on top of" or "in addition to" the traditional genetic basis
Epigenetics most often denotes changes in a
chromosome that affect gene activity and expression, but can also be
used to describe any heritable phenotypic change that does not derive
from a modification of the genome, such as prions. Such effects on
cellular and physiological phenotypic traits may result from external
or environmental factors, or be part of normal developmental program.
The standard definition of epigenetics requires these alterations to
be heritable, either in the progeny of cells or of organisms.
The term also refers to the changes themselves: functionally relevant
changes to the genome that do not involve a change in the nucleotide
sequence. Examples of mechanisms that produce such changes are DNA
methylation and histone modification, each of which alters how genes
are expressed without altering the underlying
DNA sequence. Gene
expression can be controlled through the action of repressor proteins
that attach to silencer regions of the DNA. These epigenetic changes
may last through cell divisions for the duration of the cell's life,
and may also last for multiple generations even though they do not
involve changes in the underlying
DNA sequence of the organism;
instead, non-genetic factors cause the organism's genes to behave (or
"express themselves") differently.
One example of an epigenetic change in eukaryotic biology is the
process of cellular differentiation. During morphogenesis, totipotent
stem cells become the various pluripotent cell lines of the embryo,
which in turn become fully differentiated cells. In other words, as a
single fertilized egg cell – the zygote – continues to divide, the
resulting daughter cells change into all the different cell types in
an organism, including neurons, muscle cells, epithelium, endothelium
of blood vessels, etc., by activating some genes while inhibiting the
expression of others.
Historically, some phenomena not necessarily heritable have also been
described as epigenetic. For example, the term epigenetic has been
used to describe any modification of chromosomal regions, especially
histone modifications, whether or not these changes are heritable or
associated with a phenotype. The consensus definition now requires a
trait to be heritable for it to be considered epigenetic. Misuse of
the scientific term by quack authors has created misinformation and
controversy in the public.
1.2 Waddington's canalisation, 1940s
1.3 Developmental psychology
2 Molecular basis
2.2 Techniques used to study epigenetics
3.7 Structural inheritance
3.8 Nucleosome positioning
4 Functions and consequences
Epigenetics in bacteria
6.2 Genomic imprinting
6.4 Diabetic wound healing
7 Psychology and psychiatry
7.1 Early life stress
7.5 Fear conditioning
9 See also
11 External links
The term epigenetics in its contemporary usage emerged in the 1990s,
but for some years has been used in somewhat variable meanings. A
consensus definition of the concept of epigenetic trait as "stably
heritable phenotype resulting from changes in a chromosome without
alterations in the
DNA sequence" was formulated at a Cold Spring
Harbor meeting in 2008, although alternate definitions that include
non-heritable traits are still being used.
The term epigenesis has a generic meaning "extra growth". It has been
used in English since the 17th century.
Waddington's canalisation, 1940s
From the generic meaning, and the associated adjective epigenetic, C.
H. Waddington coined the term epigenetics in 1942 as pertaining to
epigenesis, in parallel to Valentin Haecker's 'phenogenetics'
(Phänogenetik). Epigenesis in the context of the biology of that
period referred to the differentiation of cells from their initial
totipotent state in embryonic development.
When Waddington coined the term, the physical nature of genes and
their role in heredity was not known; he used it as a conceptual model
of how genes might interact with their surroundings to produce a
phenotype; he used the phrase "epigenetic landscape" as a metaphor for
biological development. Waddington held that cell fates were
established in development (canalisation) much as a marble rolls down
to the point of lowest local elevation.
Waddington suggested visualising increasing irreversibility of cell
type differentiation as ridges rising between the valleys where the
marbles (cells) are travelling. In recent times Waddington's
notion of the epigenetic landscape has been rigorously formalized in
the context of the systems dynamics state approach to the study of
cell-fate. Cell-fate determination is predicted to exhibit
certain dynamics, such as attractor-convergence (the attractor can be
an equilibrium point, limit cycle or strange attractor) or
The term "epigenetic" has also been used in developmental psychology
to describe psychological development as the result of an ongoing,
bi-directional interchange between heredity and the environment.
Interactivist ideas of development have been discussed in various
forms and under various names throughout the 19th and 20th centuries.
An early version was proposed, among the founding statements in
Karl Ernst von Baer and popularized by Ernst Haeckel. A
radical epigenetic view (physiological epigenesis) was developed by
Paul Wintrebert. Another variation, probabilistic epigenesis, was
Gilbert Gottlieb in 2003. This view encompasses all
of the possible developing factors on an organism and how they not
only influence the organism and each other, but how the organism also
influences its own development.
The developmental psychologist
Erik Erikson wrote of an epigenetic
principle in his book Identity: Youth and Crisis (1968), encompassing
the notion that we develop through an unfolding of our personality in
predetermined stages, and that our environment and surrounding culture
influence how we progress through these stages. This biological
unfolding in relation to our socio-cultural settings is done in stages
of psychosocial development, where "progress through each stage is in
part determined by our success, or lack of success, in all the
Robin Holliday defined epigenetics as "the study of the mechanisms of
temporal and spatial control of gene activity during the development
of complex organisms." Thus epigenetic can be used to describe
anything other than
DNA sequence that influences the development of an
The more recent usage of the word in science has a stricter
definition. It is, as defined by Arthur Riggs and colleagues, "the
study of mitotically and/or meiotically heritable changes in gene
function that cannot be explained by changes in
The term "epigenetics", however, has been used to describe processes
which have not been demonstrated to be heritable such as some forms of
histone modification; there are therefore attempts to redefine it in
broader terms that would avoid the constraints of requiring
heritability. For example, Adrian Bird defined epigenetics as "the
structural adaptation of chromosomal regions so as to register, signal
or perpetuate altered activity states." This definition would be
inclusive of transient modifications associated with
DNA repair or
cell-cycle phases as well as stable changes maintained across multiple
cell generations, but exclude others such as templating of membrane
architecture and prions unless they impinge on chromosome function.
Such redefinitions however are not universally accepted and are still
subject to dispute. The NIH "Roadmap
Epigenomics Project", ongoing
as of 2016, uses the following definition: "For purposes of this
program, epigenetics refers to both heritable changes in gene activity
and expression (in the progeny of cells or of individuals) and also
stable, long-term alterations in the transcriptional potential of a
cell that are not necessarily heritable."
In 2008, a consensus definition of the epigenetic trait, "stably
heritable phenotype resulting from changes in a chromosome without
alterations in the
DNA sequence", was made at a Cold Spring Harbor
The similarity of the word to "genetics" has generated many parallel
usages. The "epigenome" is a parallel to the word "genome", referring
to the overall epigenetic state of a cell, and epigenomics refers to
more global analyses of epigenetic changes across the entire
genome. The phrase "genetic code" has also been adapted—the
"epigenetic code" has been used to describe the set of epigenetic
features that create different phenotypes in different cells. Taken to
its extreme, the "epigenetic code" could represent the total state of
the cell, with the position of each molecule accounted for in an
epigenomic map, a diagrammatic representation of the gene expression,
DNA methylation and histone modification status of a particular
genomic region. More typically, the term is used in reference to
systematic efforts to measure specific, relevant forms of epigenetic
information such as the histone code or
DNA methylation patterns.
Due to the early stages of epigenetics as a science and the
sensationalism surrounding it in the public media,
David Gorski and
Adam Rutherford advised caution against proliferation of
false and pseudoscientific conclusions by new age authors who make
unfounded suggestions that a person's genes and health can be
manipulated by mind control.
Epigenetic changes modify the activation of certain genes, but not the
genetic code sequence of DNA. The microstructure (not code) of DNA
itself or the associated chromatin proteins may be modified, causing
activation or silencing. This mechanism enables differentiated cells
in a multicellular organism to express only the genes that are
necessary for their own activity. Epigenetic changes are preserved
when cells divide. Most epigenetic changes only occur within the
course of one individual organism's lifetime; however, these
epigenetic changes can be transmitted to the organism's offspring
through a process called transgenerational epigenetic inheritance.
Moreover, if gene inactivation occurs in a sperm or egg cell that
results in fertilization, this epigenetic modification may also be
transferred to the next generation.
Specific epigenetic processes include paramutation, bookmarking,
imprinting, gene silencing, X chromosome inactivation, position
DNA methylation reprogramming, transvection, maternal effects,
the progress of carcinogenesis, many effects of teratogens, regulation
of histone modifications and heterochromatin, and technical
limitations affecting parthenogenesis and cloning.
DNA damage can also cause epigenetic changes.
is very frequent, occurring on average about 60,000 times a day per
cell of the human body (see
DNA damage (naturally occurring)). These
damages are largely repaired, but at the site of a
epigenetic changes can remain. In particular, a double strand
DNA can initiate unprogrammed epigenetic gene silencing both
DNA methylation as well as by promoting silencing types of
histone modifications (chromatin remodeling - see next section).
In addition, the enzyme Parp1 (poly(ADP)-ribose polymerase) and its
product poly(ADP)-ribose (PAR) accumulate at sites of
DNA damage as
part of a repair process. This accumulation, in turn, directs
recruitment and activation of the chromatin remodeling protein ALC1
that can cause nucleosome remodeling. Nucleosome remodeling has
been found to cause, for instance, epigenetic silencing of
DNA damaging chemicals, such as benzene,
hydroquinone, styrene, carbon tetrachloride and trichloroethylene,
cause considerable hypomethylation of DNA, some through the activation
of oxidative stress pathways.
Foods are known to alter the epigenetics of rats on different
diets. Some food components epigenetically increase the levels of
DNA repair enzymes such as MGMT and MLH1 and p53. Other
food components can reduce
DNA damage, such as soy isoflavones. In one
study, markers for oxidative stress, such as modified nucleotides that
can result from
DNA damage, were decreased by a 3-week diet
supplemented with soy. A decrease in oxidative
DNA damage was also
observed 2 h after consumption of anthocyanin-rich bilberry (Vaccinium
myrtillius L.) pomace extract.
Techniques used to study epigenetics
Epigenetic research uses a wide range of molecular biological
techniques to further understanding of epigenetic phenomena, including
chromatin immunoprecipitation (together with its large-scale variants
ChIP-on-chip and ChIP-Seq), fluorescent in situ hybridization,
methylation-sensitive restriction enzymes,
methyltransferase identification (DamID) and bisulfite sequencing.
Furthermore, the use of bioinformatics methods has a role in
Several types of epigenetic inheritance systems may play a role in
what has become known as cell memory, note however that not all of
these are universally accepted to be examples of epigenetics.
Covalent modifications of either
DNA (e.g. cytosine methylation and
hydroxymethylation) or of histone proteins (e.g. lysine acetylation,
lysine and arginine methylation, serine and threonine phosphorylation,
and lysine ubiquitination and sumoylation) play central roles in many
types of epigenetic inheritance. Therefore, the word "epigenetics" is
sometimes used as a synonym for these processes. However, this can be
Chromatin remodeling is not always inherited, and not all
epigenetic inheritance involves chromatin remodeling.
DNA associates with histone proteins to form chromatin.
Because the phenotype of a cell or individual is affected by which of
its genes are transcribed, heritable transcription states can give
rise to epigenetic effects. There are several layers of regulation of
gene expression. One way that genes are regulated is through the
remodeling of chromatin.
Chromatin is the complex of
DNA and the
histone proteins with which it associates. If the way that
wrapped around the histones changes, gene expression can change as
Chromatin remodeling is accomplished through two main
The first way is post translational modification of the amino acids
that make up histone proteins.
Histone proteins are made up of long
chains of amino acids. If the amino acids that are in the chain are
changed, the shape of the histone might be modified.
DNA is not
completely unwound during replication. It is possible, then, that the
modified histones may be carried into each new copy of the DNA. Once
there, these histones may act as templates, initiating the surrounding
new histones to be shaped in the new manner. By altering the shape of
the histones around them, these modified histones would ensure that a
lineage-specific transcription program is maintained after cell
The second way is the addition of methyl groups to the DNA, mostly at
CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine
performs much like a regular cytosine, pairing with a guanine in
double-stranded DNA. However, some areas of the genome are methylated
more heavily than others, and highly methylated areas tend to be less
transcriptionally active, through a mechanism not fully understood.
Methylation of cytosines can also persist from the germ line of one of
the parents into the zygote, marking the chromosome as being inherited
from one parent or the other (genetic imprinting).
Mechanisms of heritability of histone state are not well understood;
however, much is known about the mechanism of heritability of DNA
methylation state during cell division and differentiation.
Heritability of methylation state depends on certain enzymes (such as
DNMT1) that have a higher affinity for
5-methylcytosine than for
cytosine. If this enzyme reaches a "hemimethylated" portion of DNA
5-methylcytosine is in only one of the two
DNA strands) the
enzyme will methylate the other half.
Although histone modifications occur throughout the entire sequence,
the unstructured N-termini of histones (called histone tails) are
particularly highly modified. These modifications include acetylation,
methylation, ubiquitylation, phosphorylation, sumoylation,
ribosylation and citrullination.
Acetylation is the most highly
studied of these modifications. For example, acetylation of the K14
and K9 lysines of the tail of histone H3 by histone acetyltransferase
enzymes (HATs) is generally related to transcriptional
One mode of thinking is that this tendency of acetylation to be
associated with "active" transcription is biophysical in nature.
Because it normally has a positively charged nitrogen at its end,
lysine can bind the negatively charged phosphates of the
The acetylation event converts the positively charged amine group on
the side chain into a neutral amide linkage. This removes the positive
charge, thus loosening the
DNA from the histone. When this occurs,
SWI/SNF and other transcriptional factors can bind to
DNA and allow transcription to occur. This is the "cis" model of
epigenetic function. In other words, changes to the histone tails have
a direct effect on the
DNA itself.
Another model of epigenetic function is the "trans" model. In this
model, changes to the histone tails act indirectly on the DNA. For
example, lysine acetylation may create a binding site for
chromatin-modifying enzymes (or transcription machinery as well). This
chromatin remodeler can then cause changes to the state of the
chromatin. Indeed, a bromodomain — a protein domain that
specifically binds acetyl-lysine — is found in many enzymes that
help activate transcription, including the
SWI/SNF complex. It may be
that acetylation acts in this and the previous way to aid in
The idea that modifications act as docking modules for related factors
is borne out by histone methylation as well.
Methylation of lysine 9
of histone H3 has long been associated with constitutively
transcriptionally silent chromatin (constitutive heterochromatin). It
has been determined that a chromodomain (a domain that specifically
binds methyl-lysine) in the transcriptionally repressive protein HP1
recruits HP1 to K9 methylated regions. One example that seems to
refute this biophysical model for methylation is that tri-methylation
of histone H3 at lysine 4 is strongly associated with (and required
for full) transcriptional activation. Tri-methylation in this case
would introduce a fixed positive charge on the tail.
It has been shown that the histone lysine methyltransferase (KMT) is
responsible for this methylation activity in the pattern of histones
H3 & H4. This enzyme utilizes a catalytically active site called
the SET domain (Suppressor of variegation, Enhancer of zeste,
Trithorax). The SET domain is a 130-amino acid sequence involved in
modulating gene activities. This domain has been demonstrated to bind
to the histone tail and causes the methylation of the histone.
Differing histone modifications are likely to function in differing
ways; acetylation at one position is likely to function differently
from acetylation at another position. Also, multiple modifications may
occur at the same time, and these modifications may work together to
change the behavior of the nucleosome. The idea that multiple dynamic
modifications regulate gene transcription in a systematic and
reproducible way is called the histone code, although the idea that
histone state can be read linearly as a digital information carrier
has been largely debunked. One of the best-understood systems that
orchestrates chromatin-based silencing is the
SIR protein based
silencing of the yeast hidden mating type loci HML and HMR.
DNA methylation frequently occurs in repeated sequences, and helps to
suppress the expression and mobility of 'transposable elements':
5-methylcytosine can be spontaneously deaminated (replacing
nitrogen by oxygen) to thymidine, CpG sites are frequently mutated and
become rare in the genome, except at
CpG islands where they remain
unmethylated. Epigenetic changes of this type thus have the potential
to direct increased frequencies of permanent genetic mutation. DNA
methylation patterns are known to be established and modified in
response to environmental factors by a complex interplay of at least
DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B,
the loss of any of which is lethal in mice. DNMT1 is the most
abundant methyltransferase in somatic cells, localizes to
replication foci, has a 10–40-fold preference for hemimethylated
DNA and interacts with the proliferating cell nuclear antigen
By preferentially modifying hemimethylated DNA, DNMT1 transfers
patterns of methylation to a newly synthesized strand after DNA
replication, and therefore is often referred to as the ‘maintenance'
methyltransferase. DNMT1 is essential for proper embryonic
development, imprinting and X-inactivation. To emphasize the
difference of this molecular mechanism of inheritance from the
canonical Watson-Crick base-pairing mechanism of transmission of
genetic information, the term 'Epigenetic templating' was
introduced. Furthermore, in addition to the maintenance and
transmission of methylated
DNA states, the same principle could work
in the maintenance and transmission of histone modifications and even
cytoplasmic (structural) heritable states.
Histones H3 and H4 can also be manipulated through demethylation using
histone lysine demethylase (KDM). This recently identified enzyme has
a catalytically active site called the Jumonji domain (JmjC). The
demethylation occurs when JmjC utilizes multiple cofactors to
hydroxylate the methyl group, thereby removing it. JmjC is capable of
demethylating mono-, di-, and tri-methylated substrates.
Chromosomal regions can adopt stable and heritable alternative states
resulting in bistable gene expression without changes to the DNA
sequence. Epigenetic control is often associated with alternative
covalent modifications of histones. The stability and heritability
of states of larger chromosomal regions are suggested to involve
positive feedback where modified nucleosomes recruit enzymes that
similarly modify nearby nucleosomes. A simplified stochastic model
for this type of epigenetics is found here.
It has been suggested that chromatin-based transcriptional regulation
could be mediated by the effect of small RNAs. Small interfering RNAs
can modulate transcriptional gene expression via epigenetic modulation
of targeted promoters.
Sometimes a gene, after being turned on, transcribes a product that
(directly or indirectly) maintains the activity of that gene. For
MyoD enhance the transcription of many liver- and
muscle-specific genes, respectively, including their own, through the
transcription factor activity of the proteins they encode. RNA
signalling includes differential recruitment of a hierarchy of generic
chromatin modifying complexes and
DNA methyltransferases to specific
loci by RNAs during differentiation and development. Other
epigenetic changes are mediated by the production of different splice
forms of RNA, or by formation of double-stranded
Descendants of the cell in which the gene was turned on will inherit
this activity, even if the original stimulus for gene-activation is no
longer present. These genes are often turned on or off by signal
transduction, although in some systems where syncytia or gap junctions
RNA may spread directly to other cells or nuclei by
diffusion. A large amount of
RNA and protein is contributed to the
zygote by the mother during oogenesis or via nurse cells, resulting in
maternal effect phenotypes. A smaller quantity of sperm
transmitted from the father, but there is recent evidence that this
epigenetic information can lead to visible changes in several
generations of offspring.
MicroRNAs (miRNAs) are members of non-coding RNAs that range in size
from 17 to 25 nucleotides. miRNAs regulate a large variety of
biological functions in plants and animals. So far, in 2013, about
2000 miRNAs have been discovered in humans and these can be found
online in a mi
RNA database. Each mi
RNA expressed in a cell may
target about 100 to 200 messenger RNAs that it downregulates. Most
of the downregulation of mRNAs occurs by causing the decay of the
targeted mRNA, while some downregulation occurs at the level of
translation into protein.
It appears that about 60% of human protein coding genes are regulated
by miRNAs. Many miRNAs are epigenetically regulated. About 50% of
RNA genes are associated with CpG islands, that may be repressed
by epigenetic methylation. Transcription from methylated CpG islands
is strongly and heritably repressed. Other miRNAs are
epigenetically regulated by either histone modifications or by
DNA methylation and histone modification.
In 2011, it was demonstrated that the methylation of m
RNA plays a
critical role in human energy homeostasis. The obesity-associated FTO
gene is shown to be able to demethylate
sRNAs are small (50–250 nucleotides), highly structured, non-coding
RNA fragments found in bacteria. They control gene expression
including virulence genes in pathogens and are viewed as new targets
in the fight against drug-resistant bacteria. They play an
important role in many biological processes, binding to m
protein targets in prokaryotes. Their phylogenetic analyses, for
example through sRNA–m
RNA target interactions or protein binding
properties, are used to build comprehensive databases. sRNA-gene
maps based on their targets in microbial genomes are also
Further information: Fungal prions
Prions are infectious forms of proteins. In general, proteins fold
into discrete units that perform distinct cellular functions, but some
proteins are also capable of forming an infectious conformational
state known as a prion. Although often viewed in the context of
infectious disease, prions are more loosely defined by their ability
to catalytically convert other native state versions of the same
protein to an infectious conformational state. It is in this latter
sense that they can be viewed as epigenetic agents capable of inducing
a phenotypic change without a modification of the genome.
Fungal prions are considered by some to be epigenetic because the
infectious phenotype caused by the prion can be inherited without
modification of the genome. PSI+ and URE3, discovered in yeast in 1965
and 1971, are the two best studied of this type of prion.
Prions can have a phenotypic effect through the sequestration of
protein in aggregates, thereby reducing that protein's activity. In
PSI+ cells, the loss of the Sup35 protein (which is involved in
termination of translation) causes ribosomes to have a higher rate of
read-through of stop codons, an effect that results in suppression of
nonsense mutations in other genes. The ability of Sup35 to form
prions may be a conserved trait. It could confer an adaptive advantage
by giving cells the ability to switch into a PSI+ state and express
dormant genetic features normally terminated by stop codon
Further information: Structural inheritance
In ciliates such as
Tetrahymena and Paramecium, genetically identical
cells show heritable differences in the patterns of ciliary rows on
their cell surface. Experimentally altered patterns can be transmitted
to daughter cells. It seems existing structures act as templates for
new structures. The mechanisms of such inheritance are unclear, but
reasons exist to assume that multicellular organisms also use existing
cell structures to assemble new ones.
Eukaryotic genomes have numerous nucleosomes. Nucleosome position is
not random, and determine the accessibility of
DNA to regulatory
proteins. This determines differences in gene expression and cell
differentiation. It has been shown that at least some nucleosomes are
retained in sperm cells (where most but not all histones are replaced
by protamines). Thus nucleosome positioning is to some degree
inheritable. Recent studies have uncovered connections between
nucleosome positioning and other epigenetic factors, such as DNA
methylation and hydroxymethylation.
Functions and consequences
Developmental epigenetics can be divided into predetermined and
probabilistic epigenesis. Predetermined epigenesis is a unidirectional
movement from structural development in
DNA to the functional
maturation of the protein. "Predetermined" here means that development
is scripted and predictable. Probabilistic epigenesis on the other
hand is a bidirectional structure-function development with
experiences and external molding development.
Somatic epigenetic inheritance, particularly through
DNA and histone
covalent modifications and nucleosome repositioning, is very important
in the development of multicellular eukaryotic organisms. The
genome sequence is static (with some notable exceptions), but cells
differentiate into many different types, which perform different
functions, and respond differently to the environment and
intercellular signalling. Thus, as individuals develop, morphogens
activate or silence genes in an epigenetically heritable fashion,
giving cells a memory. In mammals, most cells terminally
differentiate, with only stem cells retaining the ability to
differentiate into several cell types ("totipotency" and
"multipotency"). In mammals, some stem cells continue producing new
differentiated cells throughout life, such as in neurogenesis, but
mammals are not able to respond to loss of some tissues, for example,
the inability to regenerate limbs, which some other animals are
capable of. Epigenetic modifications regulate the transition from
neural stem cells to glial progenitor cells (for example,
differentiation into oligodendrocytes is regulated by the
deacetylation and methylation of histones. Unlike animals, plant
cells do not terminally differentiate, remaining totipotent with the
ability to give rise to a new individual plant. While plants do
utilise many of the same epigenetic mechanisms as animals, such as
chromatin remodeling, it has been hypothesised that some kinds of
plant cells do not use or require "cellular memories", resetting their
gene expression patterns using positional information from the
environment and surrounding cells to determine their fate.
Epigenetic changes can occur in response to environmental
exposure—for example, mice given some dietary supplements have
epigenetic changes affecting expression of the agouti gene, which
affects their fur color, weight, and propensity to develop
Controversial results from one study suggested that traumatic
experiences might produce an epigenetic signal that is capable of
being passed to future generations. Mice were trained, using foot
shocks, to fear a cherry blossom odor. The investigators reported that
the mouse offspring had an increased aversion to this specific
odor. They suggested epigenetic changes that increase gene
expression, rather than in
DNA itself, in a gene, M71, that governs
the functioning of an odor receptor in the nose that responds
specifically to this cherry blossom smell. There were physical changes
that correlated with olfactory (smell) function in the brains of the
trained mice and their descendants. Several criticisms were reported,
including the study's low statistical power as evidence of some
irregularity such as bias in reporting results. Due to limits of
sample size, there is a probability that an effect will not be
demonstrated to within statistical significance even if it exists. The
criticism suggested that the probability that all the experiments
reported would show positive results if an identical protocol was
followed, assuming the claimed effects exist, is merely 0.4%. The
authors also did not indicate which mice were siblings, and treated
all of the mice as statistically independent. The original
researchers pointed out negative results in the paper's appendix that
the criticism omitted in its calculations, and undertook to track
which mice were siblings in the future.
Main article: Transgenerational epigenetic inheritance
Escherichia coli bacteria
Epigenetics can affect evolution when epigenetic changes are
heritable. A sequestered germ line or
Weismann barrier is specific
to animals, and epigenetic inheritance is more common in plants and
microbes. Eva Jablonka,
Marion J. Lamb and Étienne Danchin have
argued that these effects may require enhancements to the standard
conceptual framework of the modern synthesis and have called for an
extended evolutionary synthesis. Other evolutionary
biologists have incorporated epigenetic inheritance into population
genetics models and are openly skeptical, stating that epigenetic
mechanisms such as
DNA methylation and histone modification are
genetically inherited under the control of natural
Two important ways in which epigenetic inheritance can be different
from traditional genetic inheritance, with important consequences for
evolution, are that rates of epimutation can be much faster than rates
of mutation and the epimutations are more easily reversible.
In plants, heritable
DNA methylation mutations are 100.000 times more
likely to occur compared to
DNA mutations. An epigenetically
inherited element such as the PSI+ system can act as a "stop-gap",
good enough for short-term adaptation that allows the lineage to
survive for long enough for mutation and/or recombination to
genetically assimilate the adaptive phenotypic change. The
existence of this possibility increases the evolvability of a species.
More than 100 cases of transgenerational epigenetic inheritance
phenomena have been reported in a wide range of organisms, including
prokaryotes, plants, and animals. For instance, mourning cloak
butterflies will change color through hormone changes in response to
experimentation of varying temperatures.
The filamentous fungus Neurospora crassa is a prominent model system
for understanding the control and function of cytosine methylation. In
DNA methylation is associated with relics of a genome
defense system called RIP (repeat-induced point mutation) and silences
gene expression by inhibiting transcription elongation.
The yeast prion PSI is generated by a conformational change of a
translation termination factor, which is then inherited by daughter
cells. This can provide a survival advantage under adverse conditions.
This is an example of epigenetic regulation enabling unicellular
organisms to respond rapidly to environmental stress.
Prions can be
viewed as epigenetic agents capable of inducing a phenotypic change
without modification of the genome.
Direct detection of epigenetic marks in microorganisms is possible
with single molecule real time sequencing, in which polymerase
sensitivity allows for measuring methylation and other modifications
DNA molecule is being sequenced. Several projects have
demonstrated the ability to collect genome-wide epigenetic data in
Epigenetics in bacteria
While epigenetics is of fundamental importance in eukaryotes,
especially metazoans, it plays a different role in bacteria. Most
importantly, eukaryotes use epigenetic mechanisms primarily to
regulate gene expression which bacteria rarely do. However, bacteria
make widespread use of postreplicative
DNA methylation for the
epigenetic control of DNA-protein interactions. Bacteria also use DNA
adenine methylation (rather than
DNA cytosine methylation) as an
DNA adenine methylation is important in bacteria
virulence in organisms such as Escherichia coli, Salmonella, Vibrio,
Yersinia, Haemophilus, and Brucella. In Alphaproteobacteria,
methylation of adenine regulates the cell cycle and couples gene
DNA replication. In Gammaproteobacteria, adenine
methylation provides signals for
DNA replication, chromosome
segregation, mismatch repair, packaging of bacteriophage, transposase
activity and regulation of gene expression. There exists a
genetic switch controlling
Streptococcus pneumoniae (the pneumococcus)
that allows the bacterium to randomly change its characteristics into
six alternative states that could pave the way to improved vaccines.
Each form is randomly generated by a phase variable methylation
system. The ability of the pneumococcus to cause deadly infections is
different in each of these six states. Similar systems exist in other
Epigenetics has many and varied potential medical applications.
In 2008, the
National Institutes of Health
National Institutes of Health announced that $190 million
had been earmarked for epigenetics research over the next five years.
In announcing the funding, government officials noted that epigenetics
has the potential to explain mechanisms of aging, human development,
and the origins of cancer, heart disease, mental illness, as well as
several other conditions. Some investigators, like Randy Jirtle, PhD,
of Duke University Medical Center, think epigenetics may ultimately
turn out to have a greater role in disease than genetics.
Direct comparisons of identical twins constitute an optimal model for
interrogating environmental epigenetics. In the case of humans with
different environmental exposures, monozygotic (identical) twins were
epigenetically indistinguishable during their early years, while older
twins had remarkable differences in the overall content and genomic
DNA and histone acetylation. The
twin pairs who had spent less of their lifetime together and/or had
greater differences in their medical histories were those who showed
the largest differences in their levels of
acetylation of histones H3 and H4.
Dizygotic (fraternal) and monozygotic (identical) twins show evidence
of epigenetic influence in humans.
differences that would be abundant in a singleton-based study do not
interfere with the analysis. Environmental differences can produce
long-term epigenetic effects, and different developmental monozygotic
twin subtypes may be different with respect to their susceptibility to
be discordant from an epigenetic point of view.
A high-throughput study, which denotes technology that looks at
extensive genetic markers, focused on epigenetic differences between
monozygotic twins to compare global and locus-specific changes in DNA
methylation and histone modifications in a sample of 40 monozygotic
twin pairs. In this case, only healthy twin pairs were studied,
but a wide range of ages was represented, between 3 and 74 years. One
of the major conclusions from this study was that there is an
age-dependent accumulation of epigenetic differences between the two
siblings of twin pairs. This accumulation suggests the existence of
epigenetic “drift”. Epigenetic drift is the term given to
epigenetic modifications as they occur as a direct function with age.
While age is a known risk factor for many diseases, age-related
methylation has been found to occur differentially at specific sites
along the genome. Over time, this can result in measurable differences
between biological and chronological age. Epigenetic changes have been
found to be reflective of lifestyle and may act as functional
biomarkers of disease before clinical threshold is reached.
A more recent study, where 114 monozygotic twins and 80 dizygotic
twins were analyzed for the
DNA methylation status of around 6000
unique genomic regions, concluded that epigenetic similarity at the
time of blastocyst splitting may also contribute to phenotypic
similarities in monozygotic co-twins. This supports the notion that
microenvironment at early stages of embryonic development can be quite
important for the establishment of epigenetic marks. Congenital
genetic disease is well understood and it is clear that epigenetics
can play a role, for example, in the case of
Angelman syndrome and
Prader-Willi syndrome. These are normal genetic diseases caused by
gene deletions or inactivation of the genes, but are unusually common
because individuals are essentially hemizygous because of genomic
imprinting, and therefore a single gene knock out is sufficient to
cause the disease, where most cases would require both copies to be
Further information: Genomic imprinting
Some human disorders are associated with genomic imprinting, a
phenomenon in mammals where the father and mother contribute different
epigenetic patterns for specific genomic loci in their germ
cells. The best-known case of imprinting in human disorders is
Angelman syndrome and Prader-Willi syndrome—both can be
produced by the same genetic mutation, chromosome 15q partial
deletion, and the particular syndrome that will develop depends on
whether the mutation is inherited from the child's mother or from
their father. This is due to the presence of genomic imprinting
in the region.
Beckwith-Wiedemann syndrome is also associated with
genomic imprinting, often caused by abnormalities in maternal genomic
imprinting of a region on chromosome 11.
Rett syndrome is underlain by mutations in the
MECP2 gene despite no
large-scale changes in expression of MeCP2 being found in microarray
BDNF is downregulated in the
MECP2 mutant resulting in Rett
In the Överkalix study, paternal (but not maternal) grandsons of
Swedish men who were exposed during preadolescence to famine in the
19th century were less likely to die of cardiovascular disease. If
food was plentiful, then diabetes mortality in the grandchildren
increased, suggesting that this was a transgenerational epigenetic
inheritance. The opposite effect was observed for females—the
paternal (but not maternal) granddaughters of women who experienced
famine while in the womb (and therefore while their eggs were being
formed) lived shorter lives on average.
Further information: Cancer epigenetics
A variety of epigenetic mechanisms can be perturbed in different types
of cancer. Epigenetic alterations of
DNA repair genes or cell cycle
control genes are very frequent in sporadic (non-germ line) cancers,
being significantly more common than germ line (familial) mutations in
these sporadic cancers. Epigenetic alterations are important
in cellular transformation to cancer, and their manipulation holds
great promise for cancer prevention, detection, and therapy.
Several medications which have epigenetic impact are used in several
of these diseases. These aspects of epigenetics are addressed in
Diabetic wound healing
Epigenetic modifications have given insight into the understanding of
the pathophysiology of different disease conditions. Though, they are
strongly associated with cancer, their role in other pathological
conditions are of equal importance. It appears that, the
hyperglycaemic environment could imprint such changes at the genomic
level, that macrophages are primed towards a pro-inflammatory state
and could fail to exhibit any phenotypic alteration towards the
pro-healing type. This phenomenon of altered Macrophage Polarization
is mostly associated with all the diabetic complications in a clinical
set-up. At present, several reports reveal the relevance of different
epigenetic modifications with respect to diabetic complications.
Sooner or later, with the advancements in biomedical tools, the
detection of such biomarkers as prognostic and diagnostic tools in
patients could possibly emerge out as alternative approaches. It is
noteworthy to mention here that the use of epigenetic modifications as
therapeutic targets warrant extensive preclinical as well as clinical
evaluation prior to use.
Psychology and psychiatry
Early life stress
In a groundbreaking 2003 report, Caspi and colleagues demonstrated
that in robust cohort of over one-thousand subjects assessed multiple
times from preschool to adulthood, subjects who carried one or two
copies of the short allele of the serotonin transporter promoter
polymorphism exhibited higher rates of adult depression and
suicidality when exposed to childhood maltreatment when compared to
long allele homozygotes with equal ELS exposure.
Parental nutrition, in utero exposure to stress, male-induced maternal
effects such as attraction of differential mate quality, and maternal
as well as paternal age, and offspring gender could all possibly
influence whether a germline epimutation is ultimately expressed in
offspring and the degree to which intergenerational inheritance
remains stable throughout posterity.
Addiction is a disorder of the brain's reward system which arises
through transcriptional and neuroepigenetic mechanisms and occurs over
time from chronically high levels of exposure to an addictive stimulus
(e.g., morphine, cocaine, sexual intercourse, gambling,
Transgenerational epigenetic inheritance
Transgenerational epigenetic inheritance of
addictive phenotypes has been noted to occur in preclinical
Transgenerational epigenetic inheritance
Transgenerational epigenetic inheritance of anxiety-related phenotypes
has been reported in a preclinical study using mice. In this
investigation, transmission of paternal stress-induced traits across
generations involved small non-coding
RNA signals transmitted via the
Epigenetic inheritance of depression-related phenotypes has also been
reported in a preclinical study. Inheritance of paternal
stress-induced traits across generations involved small non-coding RNA
signals transmitted via the paternal germline.
Studies on mice have shown that certain conditional fears can be
inherited from either parent. In one example, mice were conditioned to
fear a strong scent, acetophenone, by accompanying the smell with an
electric shock. Consequently, the mice learned to fear the scent of
acetophenone alone. It was discovered that this fear could be passed
down to the mice offspring. Despite the offspring never experiencing
the electric shock themselves the mice still display a fear of the
acetophenone scent, because they inherited the fear epigenetically by
DNA methylation. These epigenetic changes lasted up to
two generations without reintroducing the shock.
The two forms of heritable information, namely genetic and epigenetic,
are collectively denoted as dual inheritance. Members of the
APOBEC/AID family of cytosine deaminases may concurrently influence
genetic and epigenetic inheritance using similar molecular mechanisms,
and may be a point of crosstalk between these conceptually
Fluoroquinolone antibiotics induce epigenetic changes in mammalian
cells through iron chelation. This leads to epigenetic effects through
inhibition of α-ketoglutarate-dependent dioxygenases that require
iron as a co-factor.
Various pharmacological agents are applied for the production of
induced pluripotent stem cells (iPSC) or maintain the embryonic stem
cell (ESC) phenotypic via epigenetic approach. Adult stem cells like
bone marrow stem cells have also shown a potential to differentiate
into cardiac competent cells when treated with G9a histone
methyltransferase inhibitor BIX01294.
Pharmacy and Pharmacology portal
Contribution of epigenetic modifications to evolution
Epigenetics of neurodegenerative diseases
Synthetic genetic array
^ Dupont C, Armant DR, Brenner CA (September 2009). "Epigenetics:
definition, mechanisms and clinical perspective". Seminars in
Reproductive Medicine. 27 (5): 351–357. doi:10.1055/s-0029-1237423.
PMC 2791696 . PMID 19711245. In the original sense of this
definition, epigenetics referred to all molecular pathways modulating
the expression of a genotype into a particular phenotype. Over the
following years, with the rapid growth of genetics, the meaning of the
word has gradually narrowed.
Epigenetics has been defined and today is
generally accepted as "the study of changes in gene function that are
mitotically and/or meiotically heritable and that do not entail a
^ "Beware the pseudo gene genies". The Guardian. 19 July 2015.
^ a b Ledford H (2008). "Disputed definitions". Nature. 455 (7216):
1023–8. doi:10.1038/4551023a. PMID 18948925.
^ a b c d Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A
(2009). "An operational definition of epigenetics". Genes &
Development. 23 (7): 781–3. doi:10.1101/gad.1787609.
PMC 3959995 . PMID 19339683.
^ a b Bird A (May 2007). "Perceptions of epigenetics". Nature. 447
(7143): 396–8. Bibcode:2007Natur.447..396B. doi:10.1038/nature05913.
^ Hunter, Philip (1 May 2008). "What genes remember". Prospect
Magazine. Web.archive.org. Archived from the original on 1 May 2008.
Retrieved 26 July 2012.
^ Reik W (May 2007). "Stability and flexibility of epigenetic gene
regulation in mammalian development". Nature. 447 (7143): 425–32.
^ a b "Beware the pseudo gene genies". The Guardian.
^ a b c Moore, David S. (2015). The Developing Genome: An Introduction
Epigenetics (1st ed.). Oxford University Press.
^ a b c "Overview". NIH Roadmap
^ Oxford English Dictionary: "The word is used by W. Harvey,
Exercitationes 1651, p. 148, and in the English Anatomical
Exercitations 1653, p. 272. It is explained to mean ‘partium
super-exorientium additamentum’, ‘the additament of parts budding
one out of another’."
^ Waddington, C. H. (1942). "The epigenotype". Endeavour. 1:
18–20. "For the purpose of a study of inheritance, the
relation between phenotypes and genotypes [...] is, from a wider
biological point of view, of crucial importance, since it is the
kernel of the whole problem of development. Many geneticists have
recognized this and attempted to discover the processes involved in
the mechanism by which the genes of the genotype bring about
phenotypic effects. The first step in such an enterprise is – or
rather should be, since it is often omitted by those with an undue
respect for the powers of reason – to describe what can be seen of
the developmental processes. For enquiries of this kind, the word
'phenogenetics' was coined by Haecker [1918, Phänogenetik]. The
second and more important part of the task is to discover the causal
mechanisms at work, and to relate them as far as possible to what
experimental embryology has already revealed of the mechanics of
development. We might use the name 'epigenetics' for such studies,
thus emphasizing their relation to the concepts, so strongly
favourable to the classical theory of epigenesis, which have been
reached by the experimental embryologists. We certainly need to
remember that between genotype and phenotype, and connecting them to
each other, there lies a whole complex of developmental processes. It
is convenient to have a name for this complex: 'epigenotype' seems
^ See preformationism for historical background. Oxford English
Dictionary: "the theory that the germ is brought into existence (by
successive accretions), and not merely developed, in the process of
reproduction. [...] The opposite theory was formerly known as the
'theory of evolution'; to avoid the ambiguity of this name, it is now
spoken of chiefly as the 'theory of preformation', sometimes as that
of 'encasement' or 'emboîtement'."
^ Waddington, C. H. (1953). The
Epigenetics of Birds. Cambridge
University Press. pp. 1–. ISBN 978-1-107-44047-0.
^ Hall BK (15 January 2004). "In search of evolutionary developmental
mechanisms: the 30-year gap between 1944 and 1974". 302. 302 (1):
5–18. doi:10.1002/jez.b.20002. PMID 14760651.
^ Alvarez-Buylla ER, Chaos A, Aldana M, Benítez M, Cortes-Poza Y,
Espinosa-Soto C, Hartasánchez DA, Lotto RB, Malkin D, Escalera Santos
GJ, Padilla-Longoria P (November 3, 2008). "Floral Morphogenesis:
Stochastic Explorations of a
Gene Network Epigenetic Landscape". PLoS
ONE. 3 (11): e3626. Bibcode:2008PLoSO...3.3626A.
doi:10.1371/journal.pone.0003626 . PMC 2572848 .
^ a b Rabajante JF, Babierra AL (January 30, 2015). "Branching and
oscillations in the epigenetic landscape of cell-fate determination".
Progress in Biophysics and Molecular Biology. 117 (2–3): 240–9.
doi:10.1016/j.pbiomolbio.2015.01.006. PMID 25641423.
^ Gottlieb, G. (1991). "Epigenetic systems view of human development".
Developmental Psychology. 27 (1): 33–34.
^ Gilbert Gottlieb. Probabilistic epigenesis, Developmental Science
10:1 (2007), 1–11
^ Boeree, C. George, (1997/2006), Personality Theories, Erik Erikson
^ Erikson, Erik (1968). Identity: Youth and Crisis. Chapter 3: W.W.
Norton and Company. p. 92.
^ "Epigenetics". Bio-Medicine.org. Retrieved 21 May 2011.
^ Holliday R (Jan 30, 1990). "
Methylation and Epigenetic
Inheritance". Philosophical Transactions of the Royal Society of
London. Series B, Biological Sciences. 326 (1235): 329–338.
^ a b Riggs AD, Russo VE, Martienssen RA (1996). Epigenetic mechanisms
of gene regulation. Plainview, N.Y.: Cold Spring Harbor Laboratory
Press. ISBN 0-87969-490-4. [page needed]
^ "Epigenetics: It doesn’t mean what quacks think it means".
^ Chandler VL (February 2007). "Paramutation: from maize to mice".
Cell. 128 (4): 641–5. doi:10.1016/j.cell.2007.02.007.
^ Kovalchuk O, Baulch JE (January 2008). "Epigenetic changes and
nontargeted radiation effects—is there a link?". Environ. Mol.
Mutagen. 49 (1): 16–25. doi:10.1002/em.20361.
^ Ilnytskyy Y, Kovalchuk O (September 2011). "Non-targeted radiation
effects-an epigenetic connection". Mutat. Res. 714 (1–2): 113–25.
doi:10.1016/j.mrfmmm.2011.06.014. PMID 21784089.
^ Friedl AA, Mazurek B, Seiler DM (2012). "Radiation-induced
alterations in histone modification patterns and their potential
impact on short-term radiation effects". Front Oncol. 2: 117.
doi:10.3389/fonc.2012.00117. PMC 3445916 .
^ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A,
Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L,
Gottesman ME, Avvedimento EV (July 2007). "
homology-directed repair, and
DNA methylation". PLoS Genet. 3 (7):
e110. doi:10.1371/journal.pgen.0030110. PMC 1913100 .
^ O'Hagan HM, Mohammad HP, Baylin SB (2008). Lee JT, ed. "Double
strand breaks can initiate gene silencing and SIRT1-dependent onset of
DNA methylation in an exogenous promoter CpG island". PLoS Genet. 4
(8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723 .
^ Malanga M, Althaus FR (2005). "The role of poly(ADP-ribose) in the
DNA damage signaling network". Biochem Cell Biol. 83 (3): 354–364.
doi:10.1139/o05-038. PMID 15959561.
^ Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK,
Washburn MP, Florens L, Ladurner AG, Conaway JW, Conaway RC (August
2009). "Poly(ADP-ribosyl)ation directs recruitment and activation of
an ATP-dependent chromatin remodeler". Proc. Natl. Acad. Sci. U.S.A.
106 (33): 13770–4. Bibcode:2009PNAS..10613770G.
doi:10.1073/pnas.0906920106. PMC 2722505 .
^ Lin JC, Jeong S, Liang G, Takai D, Fatemi M, Tsai YC, Egger G,
Gal-Yam EN, Jones PA (November 2007). "Role of nucleosomal occupancy
in the epigenetic silencing of the
MLH1 CpG island". Cancer Cell. 12
(5): 432–44. doi:10.1016/j.ccr.2007.10.014. PMC 4657456 .
^ Tabish AM, Poels K, Hoet P, Godderis L (2012). Chiariotti L, ed.
"Epigenetic factors in cancer risk: effect of chemical carcinogens on
DNA methylation pattern in human TK6 cells". PLoS ONE. 7 (4):
e34674. Bibcode:2012PLoSO...734674T. doi:10.1371/journal.pone.0034674.
PMC 3324488 . PMID 22509344.
^ Burdge GC, Hoile SP, Uller T, Thomas NA, Gluckman PD, Hanson MA,
Lillycrop KA (2011). Imhof A, ed. "Progressive, transgenerational
changes in offspring phenotype and epigenotype following nutritional
transition". PLoS ONE. 6 (11): e28282. Bibcode:2011PLoSO...628282B.
doi:10.1371/journal.pone.0028282. PMC 3227644 .
^ Fang M, Chen D, Yang CS (January 2007). "Dietary polyphenols may
DNA methylation". J. Nutr. 137 (1 Suppl): 223S–228S.
^ Olaharski AJ, Rine J, Marshall BL, Babiarz J, Zhang L, Verdin E,
Smith MT (December 2005). "The flavoring agent dihydrocoumarin
reverses epigenetic silencing and inhibits sirtuin deacetylases". PLoS
Genet. 1 (6): e77. doi:10.1371/journal.pgen.0010077.
PMC 1315280 . PMID 16362078.
^ Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Majid
S, Igawa M, Dahiya R (August 2008). "Genistein mediated histone
acetylation and demethylation activates tumor suppressor genes in
prostate cancer cells". Int. J. Cancer. 123 (3): 552–60.
doi:10.1002/ijc.23590. PMID 18431742.
^ Djuric Z, Chen G, Doerge DR, Heilbrun LK, Kucuk O (October 2001).
"Effect of soy isoflavone supplementation on markers of oxidative
stress in men and women". Cancer Lett. 172 (1): 1–6.
doi:10.1016/S0304-3835(01)00627-9. PMID 11595123.
^ Kropat C, Mueller D, Boettler U, Zimmermann K, Heiss EH, Dirsch VM,
Rogoll D, Melcher R, Richling E, Marko D (March 2013). "Modulation of
Nrf2-dependent gene transcription by bilberry anthocyanins in vivo".
Mol Nutr Food Res. 57 (3): 545–50. doi:10.1002/mnfr.201200504.
^ a b Verma, M; Rogers, S; Divi, R. L; Schully, S. D; Nelson, S; Su,
L. J; Ross, S; Pilch, S; Winn, D. M; Khoury, M. J (2013). "Epigenetic
Research in Cancer Epidemiology: Trends, Opportunities, and
Challenges". Cancer Epidemiology Biomarkers & Prevention. 23 (2):
PMC 3925982 .
^ Jablonka E, Lamb MJ, Lachmann M (September 1992). "Evidence,
mechanisms and models for the inheritance of acquired
J. Theor. Biol. 158 (2): 245–268.
^ Ptashne M (April 2007). "On the use of the word 'epigenetic'". Curr.
Biol. 17 (7): R233–6. doi:10.1016/j.cub.2007.02.030.
^ Jenuwein T, Laible G, Dorn R, Reuter G (January 1998). "SET domain
proteins modulate chromatin domains in eu- and heterochromatin". Cell.
Mol. Life Sci. 54 (1): 80–93. doi:10.1007/s000180050127.
^ Slotkin RK, Martienssen R (April 2007). "
Transposable elements and
the epigenetic regulation of the genome". Nature Reviews Genetics. 8
(4): 272–85. doi:10.1038/nrg2072. PMID 17363976.
^ a b Li E, Bestor TH, Jaenisch R (June 1992). "Targeted mutation of
DNA methyltransferase gene results in embryonic lethality". Cell.
69 (6): 915–26. doi:10.1016/0092-8674(92)90611-F.
^ Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales
FA, Jones PA (June 1999). "The human
DNA methyltransferases (DNMTs) 1,
3a and 3b: coordinate m
RNA expression in normal tissues and
overexpression in tumors". Nucleic Acids Res. 27 (11): 2291–8.
doi:10.1093/nar/27.11.2291. PMC 148793 .
^ Leonhardt H, Page AW, Weier HU, Bestor TH (November 1992). "A
targeting sequence directs
DNA methyltransferase to sites of DNA
replication in mammalian nuclei". Cell. 71 (5): 865–73.
doi:10.1016/0092-8674(92)90561-P. PMID 1423634.
^ Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (September 1997).
"Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for
p21WAF1". Science. 277 (5334): 1996–2000.
doi:10.1126/science.277.5334.1996. PMID 9302295.
^ Robertson KD, Wolffe AP (October 2000). "
DNA methylation in health
and disease". Nature Reviews Genetics. 1 (1): 11–9.
doi:10.1038/35049533. PMID 11262868.
^ Li E, Beard C, Jaenisch R (November 1993). "Role for
in genomic imprinting". Nature. 366 (6453): 362–5.
^ Viens A, Mechold U, Brouillard F, Gilbert C, Leclerc P, Ogryzko V
(July 2006). "Analysis of human histone H2AZ deposition in vivo argues
against its direct role in epigenetic templating mechanisms". Mol.
Cell. Biol. 26 (14): 5325–35. doi:10.1128/MCB.00584-06.
PMC 1592707 . PMID 16809769.
^ Ogryzko VV (2008). "Erwin Schroedinger, Francis Crick and epigenetic
stability". Biol. Direct. 3: 15. doi:10.1186/1745-6150-3-15.
PMC 2413215 . PMID 18419815.
^ Nottke A, Colaiácovo MP, Shi Y (March 2009). "Developmental roles
of the histone lysine demethylases". Development. 136 (6): 879–89.
doi:10.1242/dev.020966. PMC 2692332 . PMID 19234061.
^ Rosenfeld JA, Wang Z, Schones DE, Zhao K, DeSalle R, Zhang MQ
(2009). "Determination of enriched histone modifications in non-genic
portions of the human genome". BMC Genomics. 10: 143.
doi:10.1186/1471-2164-10-143. PMC 2667539 .
^ Sneppen K, Micheelsen MA, Dodd IB (April 15, 2008). "Ultrasensitive
gene regulation by positive feedback loops in nucleosome
modification". Molecular Systems Biology. 4 (1): 182.
doi:10.1038/msb.2008.21. PMC 2387233 . PMID 18414483.
Retrieved 5 May 2014.
^ "Epigenetic cell memory". Cmol.nbi.dk. Retrieved 26 July 2012.
^ Dodd IB, Micheelsen MA, Sneppen K, Thon G (May 2007). "Theoretical
analysis of epigenetic cell memory by nucleosome modification". Cell.
129 (4): 813–22. doi:10.1016/j.cell.2007.02.053.
^ Morris KL (2008). "Epigenetic Regulation of
Gene Expression". RNA
and the Regulation of
Gene Expression: A Hidden Layer of Complexity.
Norfolk, England: Caister Academic Press.
ISBN 1-904455-25-5. [page needed]
^ Mattick JS, Amaral PP, Dinger ME, Mercer TR, Mehler MF (January
RNA regulation of epigenetic processes". BioEssays. 31 (1):
51–9. doi:10.1002/bies.080099. PMID 19154003.
^ Choi, Charles Q. (25 May 2006). "
RNA can be hereditary molecule".
The Scientist. Archived from the original on 8 February 2007.
^ a b c Bernal JE, Duran C, Papiha SS (2012). "
epigenetic regulation of human microRNAs". Cancer Lett. 331 (1):
1–10. doi:10.1016/j.canlet.2012.12.006. PMID 23246373.
^ Browse miRBase by species
^ Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J,
Bartel DP, Linsley PS, Johnson JM (2005). "Microarray analysis shows
that some microRNAs downregulate large numbers of target mRNAs".
Nature. 433 (7027): 769–773. Bibcode:2005Natur.433..769L.
doi:10.1038/nature03315. PMID 15685193.
^ Lee D, Shin C (2012). "MicroRNA-target interactions: new insights
from genome-wide approaches". Ann N Y Acad Sci. 1271: 118–28.
doi:10.1111/j.1749-6632.2012.06745.x. PMC 3499661 .
^ Friedman RC, Farh KK, Burge CB, Bartel DP (2009). "Most mammalian
mRNAs are conserved targets of microRNAs".
Genome Res. 19 (1):
92–105. doi:10.1101/gr.082701.108. PMC 2612969 .
^ Goll MG, Bestor TH (2005). "
Eukaryotic cytosine methyltransferases".
Annu Rev Biochem. 74: 481–514.
^ Guifang Jia; Ye Fu; Xu Zhao; Qing Dai; Guanqun Zheng; Ying Yang;
Chengqi Yi; Lindahl, Tomas; Tao Pan; Yun-Gui Yang; Chuan He (16
October 2011). "N6-Methyladenosine in nuclear
RNA is a major substrate
of the obesity-associated FTO". Nature Chemical Biology. 7 (12):
885–887. doi:10.1038/nchembio.687. PMC 3218240 .
^ "New research links common
RNA modification to obesity".
Physorg.com. Retrieved 26 July 2012.
^ Howden BP, Beaume M, Harrison PF, Hernandez D, Schrenzel J, Seemann
T, Francois P, Stinear TP (August 2013). "Analysis of the Small RNA
Transcriptional Response in Multidrug-Resistant Staphylococcus aureus
after Antimicrobial Exposure". Antimicrob. Agents Chemother. 57 (8):
3864–74. doi:10.1128/AAC.00263-13. PMC 3719707 .
^ sRNATarBase 2.0 A comprehensive database of bacterial S
verified by experiments Archived 26 September 2013 at the Wayback
Genomics maps for small non-coding RNA's and their targets in
^ Yool A, Edmunds WJ (1998). "Epigenetic inheritance and prions".
Journal of Evolutionary Biology. 11 (2): 241–242.
^ Cox BS (1965). "[PSI], a cytoplasmic suppressor of super-suppression
in yeast". Heredity. 20 (4): 505–521. doi:10.1038/hdy.1965.65.
^ Lacroute F (May 1971). "Non-Mendelian mutation allowing
ureidosuccinic acid uptake in yeast". J. Bacteriol. 106 (2): 519–22.
PMC 285125 . PMID 5573734.
^ Liebman SW, Sherman F (September 1979). "Extrachromosomal psi+
determinant suppresses nonsense mutations in yeast". J. Bacteriol. 139
(3): 1068–71. PMC 218059 . PMID 225301.
^ True HL, Lindquist SL (September 2000). "A yeast prion provides a
mechanism for genetic variation and phenotypic diversity". Nature. 407
(6803): 477–83. doi:10.1038/35035005. PMID 11028992.
^ Shorter J, Lindquist S (June 2005). "
Prions as adaptive conduits of
memory and inheritance". Nature Reviews Genetics. 6 (6): 435–50.
doi:10.1038/nrg1616. PMID 15931169.
^ Giacomelli MG; Hancock AS; Masel J (2007). "The conversion of 3′
UTRs into coding regions". Molecular Biology & Evolution. 24 (2):
457–464. doi:10.1093/molbev/msl172. PMC 1808353 .
^ Lancaster AK, Bardill JP, True HL, Masel J (2010). "The Spontaneous
Appearance Rate of the
Prion PSI+ and Its Implications for the
Evolution of the
Evolvability Properties of the PSI+ System".
Genetics. 184 (2): 393–400. doi:10.1534/genetics.109.110213.
PMC 2828720 . PMID 19917766.
^ Sapp J (1991). "Concepts of organization. The leverage of ciliate
protozoa". Dev. Biol. 7: 229–58. doi:10.1007/978-1-4615-6823-0_11.
^ Sapp J (2003). Genesis: the evolution of biology. Oxford
[Oxfordshire]: Oxford University Press. ISBN 0-19-515619-6.
^ Gray RD, Oyama S, Griffiths PE (2003). Cycles of Contingency:
Developmental Systems and
Evolution (Life and Mind: Philosophical
Issues in Biology and Psychology). Cambridge, Mass: The MIT Press.
^ a b Teif VB, Beshnova DA, Vainshtein Y, Marth C, Mallm JP, Höfer T,
Rippe K (8 May 2014). "Nucleosome repositioning links DNA
(de)methylation and differential CTCF binding during stem cell
Genome Research. 24: 1285–1295.
doi:10.1101/gr.164418.113. PMC 4120082 .
^ Griesemer J, Haber MH, Yamashita G, Gannett L (March 2005).
"Critical Notice: Cycles of Contingency – Developmental Systems and
Evolution". Biology & Philosophy. 20 (2–3): 517–544.
^ Chapter: "Nervous System Development" in "Epigenetics," by Benedikt
Hallgrimsson and Brian Hall
^ Costa S, Shaw P (March 2007). "'Open minded' cells: how cells can
change fate" (PDF). Trends Cell Biol. 17 (3): 101–6.
doi:10.1016/j.tcb.2006.12.005. PMID 17194589. Archived from the
original (PDF) on 15 December 2013. This might suggest that plant
cells do not use or require a cellular memory mechanism and just
respond to positional information. However, it has been shown that
plants do use cellular memory mechanisms mediated by PcG proteins in
several processes, ... (p.104)
^ Cooney CA, Dave AA, Wolff GL (August 2002). "Maternal methyl
supplements in mice affect epigenetic variation and
DNA methylation of
offspring". J. Nutr. 132 (8 Suppl): 2393S–2400S.
^ Waterland RA, Jirtle RL (August 2003). "Transposable elements:
targets for early nutritional effects on epigenetic gene regulation".
Mol. Cell. Biol. 23 (15): 5293–300.
doi:10.1128/MCB.23.15.5293-5300.2003. PMC 165709 .
^ Fearful Memories Passed Down to Mouse Descendants: Genetic imprint
from traumatic experiences carries through at least two generations,
By Ewen Callaway and Nature magazine Sunday, 1 December 2013.
^ Mice can 'warn' sons, grandsons of dangers via sperm, by Mariette Le
^ G. Francis, "Too Much Success for Recent Groundbreaking Epigenetic
^ Dias BG, Ressler KJ (2014). "Parental olfactory experience
influences behavior and neural structure in subsequent generations".
Nat. Neurosci. 17: 89–96. doi:10.1038/nn.3594. PMC 3923835 .
PMID 24292232. (see comment by Gonzalo Otazu)
^ Lamb MJ, Jablonka E (2005).
Evolution in four dimensions: genetic,
epigenetic, behavioral, and symbolic variation in the history of life.
Cambridge, Mass: MIT Press. ISBN 0-262-10107-6.
^ See also
Denis Noble The Music of Life see esp pp. 93–8 and p. 48
where he cites Jablonka & Lamb and Massimo Pigliucci's review of
Jablonka and Lamb in Nature 435, 565–566 (2 June 2005)
^ Danchin É, Charmantier A, Champagne FA, Mesoudi A, Pujol B,
Blanchet S (2011). "Beyond DNA: integrating inclusive inheritance into
an extended theory of evolution". Nature Reviews Genetics. 12:
475–486. doi:10.1038/nrg3028. PMID 21681209.
^ Maynard Smith J (1990). "Models of a Dual Inheritance System".
Journal of Theoretical Biology. 143 (1): 41–53.
doi:10.1016/S0022-5193(05)80287-5. PMID 2359317.
^ Lynch M (2007). "The frailty of adaptive hypotheses for the origins
of organismal complexity". PNAS. 104 (suppl. 1): 8597–8604.
PMC 1876435 . PMID 17494740.
^ Dickins, Thomas E.; Rahman, Qazi (2012). "The extended evolutionary
synthesis and the role of soft inheritance in evolution". Proceedings
of the Royal Society B: Biological Sciences. 279 (1740): 2913–21.
doi:10.1098/rspb.2012.0273. PMC 3385474 .
^ Rando OJ, Verstrepen KJ (February 2007). "Timescales of genetic and
epigenetic inheritance". Cell. 128 (4): 655–68.
doi:10.1016/j.cell.2007.01.023. PMID 17320504.
^ Lancaster AK, Masel J (1 September 2009). "The evolution of
reversible switches in the presence of irreversible mimics".
Evolution. 63 (9): 2350–2362. doi:10.1111/j.1558-5646.2009.00729.x.
PMC 2770902 . PMID 19486147.
^ van der Graaf, Adriaan; Wardenaar, René; Neumann, Drexel A.; Taudt,
Aaron; Shaw, Ruth G.; Jansen, Ritsert C.; Schmitz, Robert J.;
Colomé-Tatché, Maria; Johannes, Frank (2015). "Rate, spectrum, and
evolutionary dynamics of spontaneous epimutations". Proceedings of the
National Academy of Sciences. 112 (21): 6676–81.
doi:10.1073/pnas.1424254112. PMC 4450394 .
^ Úbeda, Francisco; Griswold, Cortland K.; Masel, Joanna (2009).
"Complex Adaptations Can Drive the
Evolution of the Capacitor [PSI+],
Even with Realistic Rates of
Yeast Sex". PLoS Genetics. 5 (6):
e1000517. doi:10.1371/journal.pgen.1000517. PMC 2686163 .
^ Jablonka E, Raz G (June 2009). "Transgenerational epigenetic
inheritance: prevalence, mechanisms, and implications for the study of
heredity and evolution" (PDF). Q Rev Biol. 84 (2): 131–76.
doi:10.1086/598822. PMID 19606595.
^ Davies, Hazel (2008). Do Butterflies Bite?: Fascinating Answers to
Questions about Butterflies and Moths (Animals Q&A). Rutgers
^ Lewis ZA, Honda S, Khlafallah TK, Jeffress JK, Freitag M, Mohn F,
Schübeler D, Selker EU (March 2009). "Relics of repeat-induced point
mutation direct heterochromatin formation in Neurospora crassa".
Genome Res. 19 (3): 427–37. doi:10.1101/gr.086231.108.
PMC 2661801 . PMID 19092133.
^ a b Jorg Tost (2008). Epigenetics. Norfolk, England: Caister
Academic Press. ISBN 1-904455-23-9.
^ Schadt EE, Banerjee O, Fang G, Feng Z, Wong WH, Zhang X, Kislyuk A,
Clark TA, Luong K, Keren-Paz A, Chess A, Kumar V, Chen-Plotkin A,
Sondheimer N, Korlach J, Kasarskis A (2012). "Modeling kinetic rate
variation in third generation
DNA sequencing data to detect putative
Genome Research. 23 (1): 129–41.
doi:10.1101/gr.136739.111. PMC 3530673 .
^ Davis BM, Chao MC, Waldor MK (2013). "Entering the era of bacterial
epigenomics with single molecule real time
DNA sequencing". Current
Opinion in Microbiology. 16 (2): 192–8.
doi:10.1016/j.mib.2013.01.011. PMC 3646917 .
^ Lluch-Senar M, Luong K, Lloréns-Rico V, Delgado J, Fang G, Spittle
K, Clark TA, Schadt E, Turner SW, Korlach J, Serrano L (2013).
Richardson PM, ed. "Comprehensive Methylome Characterization of
Mycoplasma genitalium and Mycoplasma pneumoniae at Single-Base
Resolution". PLoS Genetics. 9 (1): e1003191.
doi:10.1371/journal.pgen.1003191. PMC 3536716 .
^ Murray IA, Clark TA, Morgan RD, Boitano M, Anton BP, Luong K,
Fomenkov A, Turner SW, Korlach J, Roberts RJ (2012). "The methylomes
of six bacteria". Nucleic Acids Research. 40 (22): 11450–62.
doi:10.1093/nar/gks891. PMC 3526280 . PMID 23034806.
^ Fang G, Munera D, Friedman DI, Mandlik A, Chao MC, Banerjee O, Feng
Z, Losic B, Mahajan MC, Jabado OJ, Deikus G, Clark TA, Luong K, Murray
IA, Davis BM, Keren-Paz A, Chess A, Roberts RJ, Korlach J, Turner SW,
Kumar V, Waldor MK, Schadt EE (2012). "Genome-wide mapping of
methylated adenine residues in pathogenic
Escherichia coli using
single-molecule real-time sequencing". Nature Biotechnology. 30 (12):
1232–9. doi:10.1038/nbt.2432. PMC 3879109 .
^ Casadesús J, Low D (September 2006). "Epigenetic gene regulation in
the bacterial world". Microbiol. Mol. Biol. Rev. 70 (3): 830–56.
doi:10.1128/MMBR.00016-06. PMC 1594586 .
^ Manso AS, Chai MH, Atack JM, Furi L, De Ste Croix M, Haigh R,
Trappetti C, Ogunniyi AD, Shewell LK, Boitano M, Clark TA, Korlach J,
Blades M, Mirkes E, Gorban AN, Paton JC, Jennings MP, Oggioni MR
(September 2014). "A random six-phase switch regulates pneumococcal
virulence via global epigenetic changes". Nature Communications. 5:
5055. doi:10.1038/ncomms6055. PMC 4190663 .
^ Chahwan R, Wontakal SN, Roa S (March 2011). "The multidimensional
nature of epigenetic information and its role in disease". Discov Med.
11 (58): 233–43. PMID 21447282.
^ Beil, Laura (Winter 2008). "Medicine's New Epicenter? Epigenetics:
New field of epigenetics may hold the secret to flipping cancer's
"off" switch". CURE (Cancer Updates, Research and Education). Archived
from the original on 29 May 2009.
^ a b c Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar
ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M,
Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z,
Spector TD, Wu YZ, Plass C, Esteller M (July 2005). "Epigenetic
differences arise during the lifetime of monozygotic twins". Proc.
Natl. Acad. Sci. U.S.A. 102 (30): 10604–9.
PMC 1174919 . PMID 16009939.
^ Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH, Feldcamp LA,
Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery
GW, Gottesman II, Martin NG, Petronis A (February 2009). "DNA
methylation profiles in monozygotic and dizygotic twins". Nat. Genet.
41 (2): 240–5. doi:10.1038/ng.286. PMID 19151718.
^ O'Connor, Anahad (11 March 2008). "The Claim: Identical Twins Have
Identical DNA". New York Times. Retrieved 2 May 2010.
^ Ballestar E (2010). "
Epigenetics lessons from twins: prospects for
autoimmune disease". Clin Rev Allergy Immunol. 39 (1): 30–41.
doi:10.1007/s12016-009-8168-4. PMID 19653134.
^ Wallace, Robert G.; Twomey, Laura C.; Custaud, Marc-Antoine; Moyna,
Niall; Cummins, Philip M.; Mangone, Marco; Murphy, Ronan P. (2016).
"Potential Diagnostic and Prognostic Biomarkers of Epigenetic Drift
within the Cardiovascular Compartment". BioMed Research International.
2016: 2465763. doi:10.1155/2016/2465763. PMC 4749768 .
^ Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH, Feldcamp LA,
Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery
GW, Gottesman II, Martin NG, Petronis A (2009). "
profiles in monozygotic and dizygotic twins". Nat Genet. 41 (2):
240–245. doi:10.1038/ng.286. PMID 19151718.
Online Mendelian Inheritance in Man (OMIM) 105830
^ Wood AJ, Oakey RJ (November 2006). "
Genomic imprinting in mammals:
emerging themes and established theories". PLoS Genet. 2 (11): e147.
doi:10.1371/journal.pgen.0020147. PMC 1657038 .
^ Knoll JH, Nicholls RD, Magenis RE, Graham JM, Lalande M, Latt SA
(February 1989). "Angelman and Prader-Willi syndromes share a common
chromosome 15 deletion but differ in parental origin of the deletion".
Am. J. Med. Genet. 32 (2): 285–90. doi:10.1002/ajmg.1320320235.
^ A person's paternal grandson is the son of a son of that person; a
maternal grandson is the son of a daughter.
^ Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K,
Sjöström M, Golding J (February 2006). "Sex-specific, male-line
transgenerational responses in humans". Eur. J. Hum. Genet. 14 (2):
159–66. doi:10.1038/sj.ejhg.5201538. PMID 16391557.
Robert Winston refers to this study in a lecture Archived 23 May 2007
at the Wayback Machine.; see also discussion at Leeds University, here
^ "NOVA Transcripts Ghost in Your Genes". PBS. 16 October 2007.
Retrieved 26 July 2012.
^ Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, Shen D,
Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V,
Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z,
Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S,
Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB,
Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz
SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007). "The
genomic landscapes of human breast and colorectal cancers". Science.
318 (5853): 1108–1113. Bibcode:2007Sci...318.1108W.
doi:10.1126/science.1145720. PMID 17932254.
^ Jasperson KW, Tuohy TM, Neklason DW, Burt RW (2010). "Hereditary and
familial colon cancer". Gastroenterology. 138 (6): 2044–2058.
doi:10.1053/j.gastro.2010.01.054. PMC 3057468 .
^ Novak, Kris (20 December 2004). "
Epigenetics Changes in Cancer
Cells". Medscape General Medicine. 6 (4): 17. PMC 1480584 .
^ Banno K, Kisu I, Yanokura M, Tsuji K, Masuda K, Ueki A, Kobayashi Y,
Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D (2012).
"Epimutation and cancer: a new carcinogenic mechanism of Lynch
syndrome (Review)". Int. J. Oncol. 41 (3): 793–7.
doi:10.3892/ijo.2012.1528. PMC 3582986 .
^ Mallik SB, Jayashree BS, Shenoy RR. Epigenetic modulation of
macrophage polarization-perspectives in diabetic wounds. Journal of
diabetes and its complications. 2018 Feb 7.
^ Caspi, A. (18 July 2003). "Influence of Life Stress on Depression:
Moderation by a Polymorphism in the 5-HTT Gene". Science. 301 (5631):
386–389. doi:10.1126/science.1083968. PMID 12869766.
^ Persistence of Early-Life Stress on the Epigenome: Nonhuman Primate
^ Robison AJ, Nestler EJ (November 2011). "
epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11):
623–637. doi:10.1038/nrn3111. PMC 3272277 .
^ Nestler EJ (December 2013). "Cellular basis of memory for
addiction". Dialogues Clin. Neurosci. 15 (4): 431–443.
PMC 3898681 . PMID 24459410.
^ Ruffle JK (November 2014). "Molecular neurobiology of addiction:
what's all the (Δ)FosB about?". Am J Drug Alcohol Abuse. 40 (6):
428–437. doi:10.3109/00952990.2014.933840. PMID 25083822.
ΔFosB is an essential transcription factor implicated in the
molecular and behavioral pathways of addiction following repeated drug
exposure. The formation of ΔFosB in multiple brain regions, and the
molecular pathway leading to the formation of AP-1 complexes is well
understood. The establishment of a functional purpose for ΔFosB has
allowed further determination as to some of the key aspects of its
molecular cascades, involving effectors such as GluR2 (87,88), Cdk5
(93) and NFkB (100). Moreover, many of these molecular changes
identified are now directly linked to the structural, physiological
and behavioral changes observed following chronic drug exposure
(60,95,97,102). New frontiers of research investigating the molecular
roles of ΔFosB have been opened by epigenetic studies, and recent
advances have illustrated the role of ΔFosB acting on
histones, truly as a ‘‘molecular switch’’ (34). As a
consequence of our improved understanding of ΔFosB in addiction, it
is possible to evaluate the addictive potential of current medications
(119), as well as use it as a biomarker for assessing the efficacy of
therapeutic interventions (121,122,124). Some of these proposed
interventions have limitations (125) or are in their infancy (75).
However, it is hoped that some of these preliminary findings may lead
to innovative treatments, which are much needed in addiction.
^ Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka
M, Studziński T (2012). "Epigenetic regulation in drug addiction".
Ann. Agric. Environ. Med. 19 (3): 491–496. PMID 23020045. For
these reasons, ΔFosB is considered a primary and causative
transcription factor in creating new neural connections in the reward
centre, prefrontal cortex, and other regions of the limbic system.
This is reflected in the increased, stable and long-lasting level of
sensitivity to cocaine and other drugs, and tendency to relapse even
after long periods of abstinence. These newly constructed networks
function very efficiently via new pathways as soon as drugs of abuse
are further taken ... In this way, the induction of CDK5 gene
expression occurs together with suppression of the G9A gene coding for
dimethyltransferase acting on the histone H3. A feedback mechanism can
be observed in the regulation of these 2 crucial factors that
determine the adaptive epigenetic response to cocaine. This depends on
ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in
turn inhibits transcription factors for ΔFosB. For this reason, the
observed hyper-expression of G9a, which ensures high levels of the
dimethylated form of histone H3, eliminates the neuronal structural
and plasticity effects caused by cocaine by means of this feedback
which blocks ΔFosB transcription
^ Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational
inheritance of addictive-like behaviors". Neuroscience. 264:
PMC 3872494 . PMID 23920159.
^ Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, Arias-Carrión
O, Machado S, Hou G, So KF (2015). "Transgenerational Inheritance of
Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and
Metabolism". Mol. Neurobiol. doi:10.1007/s12035-015-9526-2.
^ a b Short, A K; Fennell, K A; Perreau, V M; Fox, A; O’Bryan, M K;
Kim, J H; Bredy, T W; Pang, T Y; Hannan, A J (2016). "Elevated
paternal glucocorticoid exposure alters the small noncoding RNA
profile in sperm and modifies anxiety and depressive phenotypes in the
offspring". Translational Psychiatry. 6 (6): e837.
doi:10.1038/tp.2016.109. PMC 4931607 .
^ Szyf M (2014). "Lamarck revisited: epigenetic inheritance of
ancestral odor fear conditioning". Nat. Neurosci. 17 (1): 2–4.
doi:10.1038/nn.3603. PMID 24369368.
^ Chahwan R, Wontakal SN, Roa S (October 2010). "Crosstalk between
genetic and epigenetic information through cytosine deamination".
Trends Genet. 26 (10): 443–8. doi:10.1016/j.tig.2010.07.005.
^ Badal S, Her YF, Maher LJ 3rd (Sep 2015). "Nonantibiotic Effects of
Mammalian Cells". J Biol Chem. 290: 22287–97.
doi:10.1074/jbc.M115.671222. PMC 4571980 .
PMID 26205818. CS1 maint: Multiple names: authors list
^ mezentseva, nadejda; yang, jinpu; kaur, keerat; eisenberg, carol;
eisenberg, leonard (2012). "The histone methyltransferase inhibitor
BIX01294 enhances the cardiac potential of bone marrow cells". Stem
Cells Dev. 22: 654–67. doi:10.1089/scd.2012.0181.
PMC 3564468 . PMID 22994322.
^ yang, jinpu; kaur, keerat; ong, lilin; eisenberg, carol; eisenberg,
leonard (2015). "Inhibition of G9a
Histone Methyltransferase Converts
Bone Marrow Mesenchymal Stem Cells to Cardiac Competent Progenitors".
stem cell international. 2015: 270428. doi:10.1155/2015/270428.
PMC 4454756 . PMID 26089912.
Look up epigenetics in Wiktionary, the free dictionary.
Wikimedia Commons has media related to Epigenetics.
Haque FN, Gottesman II, Wong AH (May 2009). "Not really identical:
epigenetic differences in monozygotic twins and implications for twin
studies in psychiatry". American Journal of Medical
Genetics Part C.
151C (2): 136–41. doi:10.1002/ajmg.c.30206.
The Human Epigenome Project (HEP)
The Epigenome Network of Excellence (NoE)
Canadian Epigenetics, Environment and Health Research Consortium
The Epigenome Network of Excellence (NoE)- public international site
DNA Is Not Destiny – Discover Magazine cover story
BBC – Horizon – 2005 – The Ghost In Your Genes
Epigenetics article at Hopkins Medicine
Towards a global map of epigenetic variation
the British Isles
the Near East
List of genetics research organizations
DNA → RNA → Protein
RNA (pre-mRNA / hnRNA)
Histone acetylation and deacetylation
Ribosome-nascent chain complex
Ribosome-nascent chain complex (RNC)
Post-translational modification (functional groups ·
peptides · structural changes)
Gene regulatory network
The development of phenotype
Norms of reaction
Fitness landscape/evolutionary landscape
Dual inheritance theory
Evolution of genetic systems
Evolution of sexual reproduction
Control of development
Regulation of gene expression
Gene regulatory network
Evolutionary developmental biology
Hedgehog signaling pathway
Notch signaling pathway
Cell surface receptor
C. H. Waddington
François Jacob + Jacques Monod
Eric F. Wieschaus
Sean B. Carroll
Endless Forms Most Beautiful
Nature versus nurture
Index of evolutionary biology articles
History of molecular biology
DNA replication (DNA)
Dry lab / Wet lab
Model organisms (such as
Pigment & Radioactivity
High-throughput technique ("-omics")
Molecular and cellular biology