Heterochromatin is a tightly packed form of
DNA or ''
condensed DNA'', which comes in multiple varieties. These varieties lie on a continue between the two extremes of
constitutive heterochromatin
Constitutive heterochromatin domains are regions of DNA found throughout the chromosomes of eukaryotes. The majority of constitutive heterochromatin is found at the pericentromeric regions of chromosomes, but is also found at the telomeres and thro ...
and
facultative heterochromatin
Heterochromatin is a tightly packed form of DNA or '' condensed DNA'', which comes in multiple varieties. These varieties lie on a continue between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a rol ...
. Both play a role in the
expression of genes
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. Th ...
. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously
turned over via
RNA-induced transcriptional silencing
RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules – such as small interfering RNA (siRNA) – trigger the downregulation of transcription of a particular gene or genomic region. This is us ...
(RITS). Recent studies with
electron microscopy and
OsO4 staining reveal that the dense packing is not due to the chromatin.
Constitutive heterochromatin can affect the genes near itself (e.g.
position-effect variegation Position-effect variegation (PEV) is a variegation caused by the silencing of a gene in some cells through its abnormal juxtaposition with heterochromatin via rearrangement or transposition. It is also associated with changes in chromatin conforma ...
). It is usually
repetitive and forms structural functions such as
centromeres
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers a ...
or
telomeres
A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
, in addition to acting as an attractor for other gene-expression or repression signals.
Facultative heterochromatin is the result of genes that are
silenced through a mechanism such as
histone deacetylation or
Piwi-interacting RNA
Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA, non-coding RNA molecules expressed in animal cells. piRNAs form RNA-protein complexes through interactions with piwi-subfamily Argonaute proteins. These piRNA complexes are ...
(piRNA) through
RNAi
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...
. It is not repetitive and shares the compact structure of constitutive heterochromatin. However, under specific developmental or environmental signaling cues, it can lose its condensed structure and become transcriptionally active.
Heterochromatin has been associated with the
di- and
tri -methylation of
H3K9
The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications (known as ''histone marks'') to histone proteins, primarily on their unstructured ends. Together with sim ...
in certain portions of the human genome.
H3K9me3
H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.
Nomenclature
H3K9me3 ...
-related
methyltransferase
Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Ross ...
s appear to have a pivotal role in modifying heterochromatin during lineage commitment at the onset of
organogenesis
Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...
and in maintaining lineage fidelity.
Structure
Chromatin
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
is found in two varieties:
euchromatin
Euchromatin (also called "open chromatin") is a lightly packed form of chromatin ( DNA, RNA, and protein) that is enriched in genes, and is often (but not always) under active transcription. Euchromatin stands in contrast to heterochromatin, whi ...
and heterochromatin. Originally, the two forms were distinguished cytologically by how intensely they get stained – the euchromatin is less intense, while heterochromatin stains intensely, indicating tighter packing. Heterochromatin is usually localized to the periphery of the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
* Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
.
Despite this early dichotomy, recent evidence in both animals and plants has suggested that there are more than two distinct heterochromatin states, and it may in fact exist in four or five 'states', each marked by different combinations of
epigenetic marks.
Heterochromatin mainly consists of genetically inactive
satellite sequences, and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all. Both
centromere
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...
s and
telomere
A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
s are heterochromatic, as is the
Barr body
A Barr body (named after discoverer Murray Barr) or X-chromatin is an inactive X chromosome in a cell with more than one X chromosome, rendered inactive in a process called lyonization, in species with XY sex-determination (including huma ...
of the second, inactivated
X-chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex- ...
in a female.
Function
![Heterochromatic versus euchromatic nuclei](https://upload.wikimedia.org/wikipedia/commons/2/24/Heterochromatic_versus_euchromatic_nuclei.jpg)
Heterochromatin has been associated with several functions, from gene regulation to the protection of chromosome integrity; some of these roles can be attributed to the dense packing of DNA, which makes it less accessible to protein factors that usually bind DNA or its associated factors. For example, naked double-stranded DNA ends would usually be interpreted by the cell as damaged or viral DNA, triggering
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
arrest,
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
or destruction of the fragment, such as by
endonuclease
Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (without regard to sequence), while many, typically called restriction endonucleases ...
s in bacteria.
Some regions of chromatin are very densely packed with fibers that display a condition comparable to that of the chromosome at
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
. Heterochromatin is generally clonally inherited; when a cell divides, the two daughter cells typically contain heterochromatin within the same regions of DNA, resulting in
epigenetic inheritance
Transgenerational epigenetic inheritance is the transmission of epigenetic markers from one organism to the next (i.e., from parent to child) that affects the traits of offspring without altering the primary structure of DNA (i.e. the sequence of ...
. Variations cause heterochromatin to encroach on adjacent genes or recede from genes at the extremes of domains. Transcribable material may be repressed by being positioned (in ''cis'') at these boundary domains. This gives rise to expression levels that vary from cell to cell, which may be demonstrated by
position-effect variegation Position-effect variegation (PEV) is a variegation caused by the silencing of a gene in some cells through its abnormal juxtaposition with heterochromatin via rearrangement or transposition. It is also associated with changes in chromatin conforma ...
.
Insulator sequences may act as a barrier in rare cases where constitutive heterochromatin and highly active genes are juxtaposed (e.g. the 5'HS4 insulator upstream of the chicken β-globin locus, and loci in two ''
Saccharomyces
''Saccharomyces'' is a genus of fungi that includes many species of yeasts. ''Saccharomyces'' is from Greek σάκχαρον (sugar) and μύκης (fungus) and means ''sugar fungus''. Many members of this genus are considered very important in f ...
'' spp.).
Constitutive heterochromatin
All cells of a given species package the same regions of DNA in
constitutive heterochromatin
Constitutive heterochromatin domains are regions of DNA found throughout the chromosomes of eukaryotes. The majority of constitutive heterochromatin is found at the pericentromeric regions of chromosomes, but is also found at the telomeres and thro ...
, and thus in all cells, any genes contained within the constitutive heterochromatin will be poorly
expressed. For example, all human chromosomes
1,
9,
16, and the
Y-chromosome
The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abs ...
contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres.
Facultative heterochromatin
The regions of DNA packaged in facultative heterochromatin will not be consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within are poorly expressed) may be packaged in euchromatin in another cell (and the genes within are no longer silenced). However, the formation of facultative heterochromatin is regulated, and is often associated with
morphogenesis
Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of devel ...
or
differentiation. An example of facultative heterochromatin is
X chromosome inactivation
X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...
in female mammals: one
X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed.
Among the molecular components that appear to regulate the spreading of heterochromatin are the
Polycomb-group proteins
Polycomb-group proteins (PcG proteins) are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes ...
and non-coding genes such as
Xist. The mechanism for such spreading is still a matter of controversy. The polycomb repressive complexes
PRC1
Protein Regulator of cytokinesis 1 (PRC1) is a protein that in humans is encoded by the ''PRC1'' gene and is involved in cytokinesis.
Function
PRC1 protein is expressed at relatively high levels during S and G2/M phases of the cell cycle before ...
and
PRC2
PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 (Polycomb Repressive Complex 1).
This complex has histone methyltransferase activity and pr ...
regulate
chromatin
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
compaction and gene expression and have a fundamental role in developmental processes. PRC-mediated
epigenetic aberrations are linked to
genome instability
Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneu ...
and malignancy and play a role in the
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
response,
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
and in the fidelity of
replication.
Yeast heterochromatin
''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'', or budding yeast, is a model
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
and its heterochromatin has been defined thoroughly. Although most of its genome can be characterized as euchromatin, ''S. cerevisiae'' has regions of DNA that are transcribed very poorly. These loci are the so-called silent mating type loci (HML and HMR), the rDNA (encoding ribosomal RNA), and the sub-telomeric regions.
Fission yeast (''
Schizosaccharomyces pombe
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measur ...
'') uses another mechanism for heterochromatin formation at its centromeres. Gene silencing at this location depends on components of the
RNAi
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...
pathway. Double-stranded RNA is believed to result in silencing of the region through a series of steps.
In the fission yeast ''Schizosaccharomyces pombe'', two RNAi complexes, the RITS complex and the RNA-directed RNA polymerase complex (RDRC), are part of an RNAi machinery involved in the initiation, propagation and maintenance of heterochromatin assembly. These two complexes localize in a
siRNA
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating ...
-dependent manner on chromosomes, at the site of heterochromatin assembly.
RNA polymerase II
RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryo ...
synthesizes a transcript that serves as a platform to recruit RITS, RDRC and possibly other complexes required for heterochromatin assembly.
Both RNAi and an exosome-dependent RNA degradation process contribute to heterochromatic gene silencing. These mechanisms of ''Schizosaccharomyces pombe'' may occur in other eukaryotes.
A large RNA structure called
RevCen has also been implicated in the production of siRNAs to mediate heterochromatin formation in some fission yeast.
See also
*
Centric heterochromatin
References
External links
*
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{{Authority control
Molecular genetics
Nuclear organization