opens up DNA region where transcription machinery proteins, like RNA Pol II, transcription factors and co-activators bind to turn on gene transcription. In the absence of SWI/SNF, nucleosomes can not move farther and remain tightly aligned to one another. Additional methylation by HMT and deacetylation by HDAC proteins condenses DNA around histones and thus, make DNA unavailable for binding by RNA Pol II and other activators, leading to gene silencing.
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 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, 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. 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. This is accompanied by simultaneous accumulation of
RNF8 protein and the
DNA repair protein
NBS1 which bind to
MDC1 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. 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 pre-damage level in ~ 20 min. • Inactivating mutations in
SMARCB1, 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) is the most frequently mutated chromatin remodeling ATPase in cancer. Mutations in this gene were first recognized in human cancer cell lines derived from lung. In cancer, mutations in BRG1 show an unusually high preference for missense mutations that target the ATPase domain. which lie on important functional surfaces such as the ATP pocket or DNA-binding surface. and in other haematological malignancies •
PML-
RARA fusion protein in
acute myeloid leukemia recruits histone deacetylases. This leads to repression of genes 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
glioblastomas. • 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 and high-throughput
ChIP-chip,
ChIP-Seq and
Bisulfite sequencing 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. Estrogen is well-established as a
mitogenic factor implicated in the tumorigenesis and progression of
breast cancer 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 and
ovarian cancer. • Started pivotal phase II clinical trials: •
Belinostat (PXD101) has had a phase II trial for relapsed
ovarian cancer, and reported good results for
T cell lymphoma. •
HDAC inhibitors. 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 finger domain. •
CHARGE syndrome, an autosomal dominant disorder, has been linked recently to haploinsufficiency of
CHD7, which encodes the
CHD family ATPase CHD7.
Senescence Chromatin architectural remodeling is implicated in the process of
cellular senescence, which is related to, and yet distinct from,
organismal aging. Replicative cellular senescence refers to a permanent
cell cycle 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. Additionally, there is a general pattern of canonical
histone loss, particularly in terms of the
nucleosome histones
H3 and
H4 and the linker histone
H1. ACF1 and NuRD are downregulated in senescent cells which suggests that chromatin remodeling is essential for maintaining a mitotic phenotype. Specific remodeler depletion results in activation of proliferative genes through a failure to maintain silencing. 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 ==