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Chromatin remodeling is the dynamic modification of
chromatin Chromatin is a complex of DNA and protein found in eukaryote, 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 ...
architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.


Overview

The transcriptional regulation of the genome is controlled primarily at the preinitiation stage by binding of the core transcriptional machinery proteins (namely, RNA polymerase, transcription factors, and activators and repressors) to the core promoter sequence on the coding region of the DNA. However, DNA is tightly packaged in the nucleus with the help of packaging proteins, chiefly histone proteins to form repeating units of nucleosomes which further bundle together to form condensed chromatin structure. Such condensed structure occludes many DNA regulatory regions, not allowing them to interact with transcriptional machinery proteins and regulate gene expression. To overcome this issue and allow dynamic access to condensed DNA, a process known as chromatin remodeling alters nucleosome architecture to expose or hide regions of DNA for transcriptional regulation. By definition, chromatin remodeling is the enzyme-assisted process to facilitate access of nucleosomal DNA by remodeling the structure, composition and positioning of nucleosomes.


Classification

Access to nucleosomal DNA is governed by two major classes of protein complexes: # Covalent histone-modifying complexes. # ATP-dependent chromatin remodeling complexes.


Covalent histone-modifying complexes

Specific protein complexes, known as histone-modifying complexes catalyze addition or removal of various chemical elements on histones. These enzymatic modifications include acetylation,
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
,
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
, and ubiquitination and primarily occur at N-terminal histone tails. Such modifications affect the binding affinity between histones and DNA, and thus loosening or tightening the condensed DNA wrapped around histones, e.g., Methylation of specific lysine residues in H3 and H4 causes further condensation of DNA around histones, and thereby prevents binding of transcription factors to the DNA that lead to gene repression. On the contrary, histone acetylation relaxes chromatin condensation and exposes DNA for TF binding, leading to increased gene expression.


Known modifications

Well characterized modifications to histones include: *
Methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
Both lysine and arginine residues are known to be methylated. Methylated lysines are the best understood marks of the histone code, as specific methylated lysine match well with gene expression states. Methylation of lysines H3K4 and H3K36 is correlated with transcriptional activation while demethylation of H3K4 is correlated with silencing of the genomic region. Methylation of lysines H3K9 and H3K27 is correlated with transcriptional repression. Particularly, H3K9me3 is highly correlated with constitutive heterochromatin. * Acetylation - by HAT (histone acetyl transferase); deacetylation - by
HDAC Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
(histone deacetylase) Acetylation tends to define the 'openness' of
chromatin Chromatin is a complex of DNA and protein found in eukaryote, 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 ...
as acetylated histones cannot pack as well together as deacetylated histones. *
Phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
* Ubiquitination However, there are many more histone modifications, and sensitive
mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a '' mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is u ...
approaches have recently greatly expanded the catalog.


''Histone code'' hypothesis

The ''
histone code 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 ...
'' is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as
DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts ...
it is part of the epigenetic code. Cumulative evidence suggests that such code is written by specific enzymes which can (for example) methylate or acetylate DNA ('writers'), removed by other enzymes having demethylase or deacetylase activity ('erasers'), and finally readily identified by proteins ('readers') that are recruited to such histone modifications and bind via specific domains, e.g., bromodomain, chromodomain. These triple action of 'writing', 'reading' and 'erasing' establish the favorable local environment for transcriptional regulation, DNA-damage repair, etc. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. A very basic summary of the histone code for gene expression status is given below (histone nomenclature is described
here Here is an adverb that means "in, on, or at this place". It may also refer to: Software * Here Technologies, a mapping company * Here WeGo (formerly Here Maps), a mobile app and map website by Here Television * Here TV (formerly "here!"), a ...
):


ATP-dependent chromatin remodeling

ATP-dependent chromatin-remodeling complexes regulate gene expression by either moving, ejecting or restructuring nucleosomes. These protein complexes have a common ATPase domain and energy from the hydrolysis of ATP allows these remodeling complexes to reposition nucleosomes (often referred to as "nucleosome sliding") along the DNA, eject or assemble histones on/off of DNA or facilitate exchange of histone variants, and thus creating nucleosome-free regions of DNA for gene activation. Also, several remodelers have DNA-translocation activity to carry out specific remodeling tasks. All ATP-dependent chromatin-remodeling complexes possess a sub unit of ATPase that belongs to the SNF2 superfamily of proteins. In association to the sub unit's identity, two main groups have been classified for these proteins. These are known as the SWI2/SNF2 group and the imitation SWI (ISWI) group. The third class of ATP-dependent complexes that has been recently described contains a Snf2-like ATPase and also demonstrates deacetylase activity.


Known chromatin remodeling complexes

There are at least four families of chromatin remodelers in eukaryotes: SWI/SNF, ISWI,
NuRD In the field of molecular biology, the Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex, is a group of associated proteins with both ATP-dependent chromatin remodeling and histone deacetylase activities. , Mi-2/NuRD was the only known protei ...
/Mi-2/ CHD, and INO80 with first two remodelers being very well studied so far, especially in the yeast model. Although all of remodelers share common ATPase domain, their functions are specific based on several biological processes (DNA repair, apoptosis, etc.). This is due to the fact that each remodeler complex has unique protein domains ( Helicase,
bromodomain A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the ''N''-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducin ...
, etc.) in their catalytic ATPase region and also has different recruited subunits.


Specific functions

* Several in-vitro experiments suggest that ISWI remodelers organize nucleosome into proper bundle form and create equal spacing between nucleosomes, whereas SWI/SNF remodelers disorder nucleosomes. * The ISWI-family remodelers have been shown to play central roles in chromatin assembly after DNA replication and maintenance of higher-order chromatin structures. * INO80 and SWI/SNF-family remodelers participate in DNA double-strand break (DSB) repair and nucleotide-excision repair (NER) and thereby plays crucial role in TP53 mediated DNA-damage response. * NuRD/Mi-2/ CHD remodeling complexes primarily mediate transcriptional repression in the nucleus and are required for the maintenance of pluripotency of embryonic stem cells.


Significance


In normal biological processes

Chromatin remodeling plays a central role in the regulation of gene expression by providing the transcription machinery with dynamic access to an otherwise tightly packaged genome. Further, nucleosome movement by chromatin remodelers is essential to several important biological processes, including chromosome assembly and segregation, DNA replication and repair, embryonic development and pluripotency, and cell-cycle progression. Deregulation of chromatin remodeling causes loss of transcriptional regulation at these critical check-points required for proper cellular functions, and thus causes various disease syndromes, including cancer.


Response to DNA damage

Chromatin relaxation is one of the earliest cellular responses to DNA damage. Several experiments have been performed on the recruitment
kinetics Kinetics ( grc, κίνησις, , kinesis, ''movement'' or ''to move'') may refer to: Science and medicine * Kinetics (physics), the study of motion and its causes ** Rigid body kinetics, the study of the motion of rigid bodies * Chemical kin ...
of proteins involved in the response to DNA damage. The relaxation appears to be initiated by PARP1, whose accumulation at DNA damage is half complete by 1.6 seconds after DNA damage occurs. This is quickly followed by accumulation of chromatin remodeler
Alc1 Chromodomain-helicase-DNA-binding protein 1-like (ALC1) is an enzyme that in humans is encoded by the ''CHD1L'' gene. It has been implicated in chromatin remodeling and DNA relaxation process required for DNA replication, repair and transcriptio ...
, which has an ADP-ribose–binding domain, allowing it to be quickly attracted to the product of PARP1. The maximum recruitment of Alc1 occurs within 10 seconds of DNA damage. About half of the maximum chromatin relaxation, presumably due to action of Alc1, occurs by 10 seconds. PARP1 action at the site of a double-strand break allows recruitment of the two DNA repair enzymes MRE11 and NBS1. Half maximum recruitment of these two
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 d ...
enzymes takes 13 seconds for MRE11 and 28 seconds for NBS1. Another process of chromatin relaxation, after formation of a DNA double-strand break, employs γH2AX, the phosphorylated form of the
H2AX H2A histone family member X (usually abbreviated as H2AX) is a type of histone protein from the H2A family encoded by the ''H2AFX'' gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear. In humans ...
protein. The
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
variant H2AX constitutes about 10% of the H2A histones in human chromatin. γH2AX (phosphorylated on serine 139 of H2AX) was detected at 20 seconds after irradiation of cells (with DNA double-strand break formation), and half maximum accumulation of γH2AX occurred in one minute. The extent of chromatin with phosphorylated γH2AX is about two million base pairs at the site of a DNA double-strand break. γH2AX does not, by itself, cause chromatin decondensation, but within seconds of irradiation the protein "Mediator of the DNA damage checkpoint 1" (
MDC1 Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the ''MDC1'' gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle chec ...
) specifically attaches to γH2AX. This is accompanied by simultaneous accumulation of RNF8 protein and the
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 d ...
protein NBS1 which bind to
MDC1 Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the ''MDC1'' gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle chec ...
as MDC1 attaches to γH2AX. RNF8 mediates extensive chromatin decondensation, through its subsequent interaction with CHD4 protein, a component of the nucleosome remodeling and deacetylase complex
NuRD In the field of molecular biology, the Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex, is a group of associated proteins with both ATP-dependent chromatin remodeling and histone deacetylase activities. , Mi-2/NuRD was the only known protei ...
. CHD4 accumulation at the site of the double-strand break is rapid, with half-maximum accumulation occurring by 40 seconds after irradiation. The fast initial chromatin relaxation upon DNA damage (with rapid initiation of DNA repair) is followed by a slow recondensation, with chromatin recovering a compaction state close to its predamage level in ~ 20 min.


Cancer

Chromatin remodeling provides fine-tuning at crucial cell growth and division steps, like cell-cycle progression, DNA repair and chromosome segregation, and therefore exerts tumor-suppressor function. Mutations in such chromatin remodelers and deregulated covalent histone modifications potentially favor self-sufficiency in cell growth and escape from growth-regulatory cell signals - two important hallmarks of
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. * Inactivating mutations in
SMARCB1 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the ''SMARCB1'' gene. Function The protein encoded by this gene is part of a complex that relieves repressi ...
, formerly known as hSNF5/INI1 and a component of the human SWI/SNF remodeling complex have been found in large number of rhabdoid tumors, commonly affecting pediatric population. Similar mutations are also present in other childhood cancers, such as choroid plexus carcinoma, medulloblastoma and in some acute leukemias. Further, mouse knock-out studies strongly support SMARCB1 as a tumor suppressor protein. Since the original observation of SMARCB1 mutations in rhabdoid tumors, several more subunits of the human SWI/SNF chromatin remodeling complex have been found mutated in a wide range of neoplasms. * The SWI/SNF ATPase BRG1 (or
SMARCA4 Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the ''SMARCA4'' gene. Function The protein encoded by this gene is a member of the SWI/SNF family of proteins and ...
) is the most frequently mutated chromatin remodeling ATPase in cancer. Mutations in this gene were first recognized in human cancer cell lines derived from adrenal gland and lung. In cancer, mutations in BRG1 show an unusually high preference for missense mutations that target the ATPase domain. Mutations are enriched at highly conserved ATPase sequences, which lie on important functional surfaces such as the ATP pocket or DNA-binding surface. These mutations act in a genetically dominant manner to alter chromatin regulatory function at enhancers and promoters. * PML-RAR fusion protein in acute myeloid leukemia recruits histone deacetylases. This leads to repression of gene responsible for myelocytes to differentiate, leading to leukemia. * Tumor suppressor Rb protein functions by the recruitment of the human homologs of the SWI/SNF enzymes BRG1, histone deacetylase and DNA methyltransferase. Mutations in BRG1 are reported in several cancers causing loss of tumor suppressor action of Rb. * Recent reports indicate DNA hypermethylation in the promoter region of major tumor suppressor genes in several cancers. Although few mutations are reported in histone methyltransferases yet, correlation of DNA hypermethylation and histone H3 lysine-9 methylation has been reported in several cancers, mainly in colorectal and breast cancers. * Mutations in Histone Acetyl Transferases (HAT) p300 (missense and truncating type) are most commonly reported in colorectal, pancreatic, breast and gastric carcinomas. Loss of heterozygosity in coding region of p300 (chromosome 22q13) is present in large number of
glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
s. * Further, HATs have diverse role as transcription factors beside having histone acetylase activity, e.g., HAT subunit, hADA3 may act as an adaptor protein linking transcription factors with other HAT complexes. In the absence of hADA3, TP53 transcriptional activity is significantly reduced, suggesting role of hADA3 in activating TP53 function in response to DNA-damage. * Similarly, TRRAP, the human homolog to yeast Tra1, has been shown to directly interact with c-Myc and E2F1 - known oncoproteins.


Cancer genomics

Rapid advance in
cancer genomics Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer. Cancer is a genetic disease caused by accumulation of DNA mutations and epigenetic alter ...
and high-throughput ChIP-chip, ChIP-Seq and
Bisulfite sequencing Bisulfite sequencing (also known as bisulphite sequencing) is the use of bisulfite treatment of DNA before routine sequencing to determine the pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the mo ...
methods are providing more insight into role of chromatin remodeling in transcriptional regulation and role in cancer.


Therapeutic intervention

Epigenetic instability caused by deregulation in chromatin remodeling is studied in several cancers, including breast cancer, colorectal cancer, pancreatic cancer. Such instability largely cause widespread silencing of genes with primary impact on tumor-suppressor genes. Hence, strategies are now being tried to overcome epigenetic silencing with synergistic combination of HDAC inhibitors or HDI and DNA-demethylating agents. HDIs are primarily used as adjunct therapy in several cancer types. HDAC inhibitors can induce p21 (WAF1) expression, a regulator of p53's tumor suppressoractivity. HDACs are involved in the pathway by which the retinoblastoma protein (pRb) suppresses
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation r ...
. Estrogen is well-established as a mitogenic factor implicated in the tumorigenesis and progression of
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
via its binding to the estrogen receptor alpha (ERα). Recent data indicate that chromatin inactivation mediated by HDAC and DNA methylation is a critical component of ERα silencing in human breast cancer cells. * Approved usage: ** Vorinostat was licensed by the U.S. FDA in October 2006 for the treatment of cutaneous T cell lymphoma (CTCL). ** Romidepsin (trade name Istodax) was licensed by the US FDA in Nov 2009 for cutaneous T-cell lymphoma (CTCL). * Phase III Clinical trials: ** Panobinostat (LBH589) is in clinical trials for various cancers including a phase III trial for cutaneous T cell lymphoma (CTCL). ** Valproic acid (as Mg valproate) in phase III trials for
cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
and
ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
. * Started pivotal phase II clinical trials: **
Belinostat Belinostat (trade name Beleodaq, previously known as PXD101) is a histone deacetylase inhibitor drug developed by TopoTarget for the treatment of hematological malignancies and solid tumors. It was approved in July 2014 by the US FDA to treat p ...
(PXD101) has had a phase II trial for relapsed
ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
, and reported good results for T cell lymphoma. **
HDAC inhibitors Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...
. Current front-runner candidates for new drug targets are Histone Lysine Methyltransferases (KMT) and Protein Arginine Methyltransferases (PRMT).


Other disease syndromes

* ATRX-syndrome (α-thalassemia X-linked mental retardation) and α-thalassemia myelodysplasia syndrome are caused by mutations in ATRX, a SNF2-related ATPase with a PHD. *
CHARGE syndrome CHARGE syndrome (formerly known as CHARGE association) is a rare syndrome caused by a genetic disorder. First described in 1979, the acronym "CHARGE" came into use for newborn children with the congenital features of coloboma of the eye, heart ...
, an autosomal dominant disorder, has been linked recently to haploinsufficiency of
CHD7 Chromodomain-helicase-DNA-binding protein 7 also known as ATP-dependent helicase CHD7 is an enzyme that in humans is encoded by the ''CHD7'' gene. CHD7 is an ATP-dependent chromatin remodeler homologous to the Drosophila trithorax-group protei ...
, which encodes the CHD family ATPase CHD7.


Senescence

Chromatin architectural remodeling is implicated in the process of
cellular senescence Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approxim ...
, which is related to, and yet distinct from, organismal aging. Replicative cellular senescence refers to a permanent
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 sub ...
arrest where post- mitotic cells continue to exist as metabolically active cells but fail to proliferate. Senescence can arise due to age associated degradation, telomere attrition, progerias, pre-malignancies, and other forms of damage or disease. Senescent cells undergo distinct repressive phenotypic changes, potentially to prevent the proliferation of damaged or cancerous cells, with modified chromatin organization, fluctuations in remodeler abundance, and changes in epigenetic modifications. Senescent cells undergo chromatin landscape modifications as constitutive
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 ...
migrates to the center of the nucleus and displaces euchromatin and facultative heterochromatin to regions at the edge of the nucleus. This disrupts chromatin-
lamin Lamins, also known as nuclear lamins are fibrous proteins in type V intermediate filaments, providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with inner nuclear membrane proteins to form th ...
interactions and inverts of the pattern typically seen in a mitotically active cell. Individual Lamin-Associated Domains (LADs) and Topologically Associating Domains (TADs) are disrupted by this migration which can affect cis interactions across the genome. Additionally, there is a general pattern of canonical
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
loss, particularly in terms of the
nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundame ...
histones H3 and H4 and the linker histone H1. Histone variants with two exons are upregulated in senescent cells to produce modified nucleosome assembly which contributes to chromatin permissiveness to senescent changes. Although transcription of variant histone proteins may be elevated, canonical histone proteins are not expressed as they are only made during the
S phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
of the cell cycle and senescent cells are post-mitotic. During senescence, portions of
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
s can be exported from the nucleus for lysosomal degradation which results in greater organizational disarray and disruption of chromatin interactions. Chromatin remodeler abundance may be implicated in cellular senescence as knockdown or
knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving strikin ...
of ATP-dependent remodelers such as NuRD, ACF1, and SWI/SNP can result in DNA damage and senescent phenotypes in yeast, ''C. elegans,'' mice, and human cell cultures. ACF1 and NuRD are downregulated in senescent cells which suggests that chromatin remodeling is essential for maintaining a mitotic phenotype. Genes involved in signaling for senescence can be silenced by chromatin confirmation and polycomb repressive complexes as seen in PRC1/PCR2 silencing of p16. Specific remodeler depletion results in activation of proliferative genes through a failure to maintain silencing. Some remodelers act on enhancer regions of genes rather than the specific loci to prevent re-entry into the cell cycle by forming regions of dense heterochromatin around regulatory regions. Senescent cells undergo widespread fluctuations in epigenetic modifications in specific chromatin regions compared to mitotic cells. Human and murine cells undergoing replicative senescence experience a general global decrease in methylation; however, specific loci can differ from the general trend. Specific chromatin regions, especially those around the promoters or enhancers of proliferative loci, may exhibit elevated methylation states with an overall imbalance of repressive and activating histone modifications. Proliferative genes may show increases in the repressive mark H3K27me3 while genes involved in silencing or aberrant histone products may be enriched with the activating modification H3K4me3. Additionally, upregulating histone deacetylases, such as members of the sirtuin family, can delay senescence by removing acetyl groups that contribute to greater chromatin accessibility. General loss of methylation, combined with the addition of acetyl groups results in a more accessible chromatin conformation with a propensity towards disorganization when compared to mitotically active cells. General loss of histones precludes addition of histone modifications and contributes changes in enrichment in some chromatin regions during senescence.


See also

*
Epigenetics In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
*
Histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
* Nucleosomes *
Chromatin Chromatin is a complex of DNA and protein found in eukaryote, 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 ...
*
Histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
* Transcription factors *
CAF-1 Chromatin assembly factor-1 (CAF-1) is a protein complex — including Chaf1a (p150),   Chaf1b (p60), and p48 subunits in humans, or Cac1, Cac2, and Cac3, respectively, in yeast— that assembles histone tetramers onto replicating DNA during the ...
(Chromatin assembly factor-1) - histone chaperone that execute a coordinating role in сhromatin remodeling.


References


Further reading

*


External links


MBInfo - Chromatin

MBInfo - DNA Packaging

YouTube - Chromatin, Histones and Modifications

YouTube - Epigenetics Overview
* {{Transcription Gene expression Cancer Epigenetics Nuclear organization