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* 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.
* 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
* 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.
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.
====Cancer Genomics====
Rapid advance in cancer genomics and high-throughput [[ChIP-chip]], [[ChIP-Seq]] and [[Bisulfite_sequencing|Bisulfite sequencing]] methods are providing more insight into role of chromatin remodeling in transcriptional regulation and role in cancer.


====Therapeutic intervention====
====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 wide-spread 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|HDAC inhibitors or HDI]] and [[DNA_demethylation|DNA-demethylating agents]].
xyz


HDIs are primarily used as adjunct therapy in several cancer types.<ref>{{cite journal|author=Marks PA, Dokmanovic M |title=Histone deacetylase inhibitors: discovery and development as anticancer agents|journal=Expert opinion on investigational drugs |volume=14 |issue=12 |pages=1497–511 |year=2005|doi=10.1517/13543784.14.12.1497 |pmid=16307490}}</ref><ref>http://clincancerres.aacrjournals.org/content/8/3/662.full.pdf"Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment" 2002</ref> HDAC inhibitors can induce [[p21]] (WAF1) expression, a regulator of [[p53]]'s [[tumor suppressor gene|tumor suppressor]]activity. HDACs are involved in the pathway by which the [[retinoblastoma protein]] (pRb) suppresses [[cell proliferation]].<ref>{{cite journal |author=Richon VM, Sandhoff TW, Rifkind RA, Marks PA |title=Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation |journal=Proc. Natl. Acad. Sci. U.S.A.|volume=97 |issue=18 |pages=10014–9 |year=2000 |month=August |pmid=10954755 |pmc=27656 |doi=10.1073/pnas.180316197|url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10954755}}</ref> The pRb protein is part of a complex that attracts HDACs to the [[chromatin]] so that it will deacetylate histones.<ref name=Brehm>{{cite journal |author=Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T |title=Retinoblastoma protein recruits histone deacetylase to repress transcription |journal=Nature |volume=391 |issue=6667 |pages=597–601 |year=1998 |month=February |pmid=9468139|doi=10.1038/35404 }}</ref> Estrogens 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.<ref>{{cite journal |author=Zhang Z, Yamashita H, Toyama T, ''et al.'' |title=Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast* |journal=Breast Cancer Res. Treat. |volume=94 |issue=1 |pages=11–6|year=2005 |month=November |pmid=16172792 |doi=10.1007/s10549-005-6001-1 }}</ref>

====Approved====
*[[Vorinostat]] was licenced by the [[Food and Drug Administration (United States)|U.S. FDA]] in October 2006 for the treatment of [[cutaneous T cell lymphoma]] (CTCL).
*[[Romidepsin]] (trade name Istodax) was licenced by the US FDA in Nov 2009 for cutaneous T-cell lymphoma (CTCL),


===Other disease syndromes===
===Other disease syndromes===

Revision as of 06:57, 14 May 2012

Currently updating this wiki stub. It will be online with updated contents on May 14, 2012 0800 CDT.

Chromatin remodeling is the dynamic modification of chromatin 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, i.e., 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, e.g., 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 region 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:

  1. Covalent histone modifications.
  2. ATP-dependent chromatin remodeling complexes.

Covalent histone modifications

Specific protein complexes, known as histone-modifying complexes catalyze addition or removal of various chemical elements on histones. These enzymatic modifications include acetylation, methylation, phosphorylation, and ubiquitination and primarily occur at N-terminal histone tails. Such modifications affect the binding affinity between histones and DNA, and thus loosening and 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 preventing binding of transcription factors to the DNA leading to gene repression. On contrary, histone acetylation relaxes chromatin condensation and exposes DNA for TF binding, leading to increase gene expression. [1]

Known modifications

Well characterized modifications to histones include[2]:

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.[3] Particularly, H3K9me3 is highly correlated with constitutive heterochromatin.[4]

  • Acetylation - by HAT (histone acetyl transferase); deacetylation - by HDAC (histone deacetylase)

Acetylation tends to define the ‘openness’ of chromatin as acetylated histones cannot pack as well together as deacetylated histones.

However there are many more histone modifications, and sensitive mass spectrometry approaches have recently greatly expanded the catalog[5].

Histone Code hypothesis

The histone code 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 it is part of the epigenetic code.

Cumulative evidences suggest that such code is 1) written by specific enzymes which can (for example) methylate or acetylate DNA ('writers'), 2) removed by other enzymes having demthylase or deacetylase activity ('erasers'), and finally 3) 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.[6]

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):

Type of
modification 		Histone
H3K4 H3K9 H3K14 H3K27 H3K79 H4K20 H2BK5
mono-methylation activation[7] activation[8] activation[8] activation[8][9] activation[8] activation[8]
di-methylation repression[3] repression[3] activation[9]
tri-methylation activation[10] repression[8] repression[8] activation,[9]
repression[8] 		repression[3]
acetylation activation[10] activation[10]

ATP-dependent chromatin remodeling

ATP-dependent chromatin-remodeling complexes regulate gene expression by either by 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 (slide, twist or loop) nucleosomes along the DNA, expel histones away from DNA or facilitate exchange of histone variants, and thus creating nucleosome-free regions of DNA for gene activation. [11] Also, several remodelers have DNA-translocation activity to carry out specific remodeling tasks. [12]

Known Chromatin Remodeling Complexes

There are at least five families of chromatin remodelers in eukaryotes : SWI/SNF, ISWI, NURD/Mi-2/CHD, INO80 and SWR1 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, 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 as well as required for the maintenance of pluripotency of embryonic stem cells.[11]

Significance

In Normal Biological Processes

Chromatin remodeling is the core mechanism in regulation of gene expression by providing dynamic access of otherwise tightly packaged and sequestrated genome to the transcription machinery proteins. Further, chromatin remodelers assisted nucleosome movement is essential in several important biological processes, e.g., chromosome assembly and segregation, DNA replication and repair, embryonic development and pluripotency, cell-cycle progression and TP53 mediated DNA-damage response, etc. Deregulation of chromatin remodeling causes loss of transcriptional regulation at these critical check-points required for the healthy cellular functions, and thus causes various disease syndromes, including cancer.

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 the cancer. [13]

  • An aggressive rhabdoid tumor, found mainly in pediatric population is a cancer of brain and soft tissue. Inactivating mutations in hSNF5/INI1, a component of the SWI2/SNF2 remodeler 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 hSNF5/INI1 as a tumor suppressor protein.
  • 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 wide-spread 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.[14][15] 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.[16] The pRb protein is part of a complex that attracts HDACs to the chromatin so that it will deacetylate histones.[17] Estrogens well-established as a mitogenic factorimplicated 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.[18]

Approved

Other disease syndromes

xyz

See also

xyz This is performed by chromatin remodeling complexes like SWI/SNF[19] (human, yeast), RSC (yeast) and Imitation SWI complexes (fly).

At the core of a chromatin remodeling complex is an ATPase capable of DNA translocation.

By moving nucleosomes, proteins like transcription factors can get access to DNA that was previously unavailable, wrapped around nucleosome cores.[12]

References

  1. ^ Wang GG, Allis CD, Chi P. (2007). "Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling". Trends Mol Med. 13: 363. PMID 17822958.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Strahl B, Allis C (2000). "The language of covalent histone modifications". Nature. 403 (6765): 41–5. doi:10.1038/47412. PMID 10638745.
  3. ^ a b c d Rosenfeld, Jeffrey A; Wang, Zhibin; Schones, Dustin; Zhao, Keji; DeSalle, Rob; Zhang, Michael Q (31 March 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. PMID 19335899. {{cite journal}}: Unknown parameter |unused_data= ignored (help)CS1 maint: unflagged free DOI (link) Cite error: The named reference "Rosenfeld_2009" was defined multiple times with different content (see the help page).
  4. ^ Hublitz, Philip; Albert, Mareike; Peters, Antoine (28 April 2009). "Mechanisms of Transcriptional Repression by Histone Lysine Methylation". The International Journal of Developmental Biology. 10 (1387). Basel: 335–354. ISSN 1696-3547.
  5. ^ Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E; et al. (2011). "Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification". Cell. 146 (6): 1016–28. doi:10.1016/j.cell.2011.08.008. PMC 3176443. PMID 21925322. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  6. ^ Jenuwein T, Allis C (2001). "Translating the histone code". Science. 293 (5532): 1074–80. doi:10.1126/science.1063127. PMID 11498575.
  7. ^ Benevolenskaya EV (2007). "Histone H3K4 demethylases are essential in development and differentiation". Biochem. Cell Biol. 85 (4): 435–43. doi:10.1139/o07-057. PMID 17713579. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ a b c d e f g h Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007). "High-resolution profiling of histone methylations in the human genome". Cell. 129 (4): 823–37. doi:10.1016/j.cell.2007.05.009. PMID 17512414. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ a b c Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, Vakoc AL, Kim JE, Chen J, Lazar MA, Blobel GA, Vakoc CR (2008). "DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells". Mol. Cell. Biol. 28 (8): 2825–39. doi:10.1128/MCB.02076-07. PMC 2293113. PMID 18285465. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ a b c Koch CM, Andrews RM, Flicek P, Dillon SC, Karaöz U, Clelland GK, Wilcox S, Beare DM, Fowler JC, Couttet P, James KD, Lefebvre GC, Bruce AW, Dovey OM, Ellis PD, Dhami P, Langford CF, Weng Z, Birney E, Carter NP, Vetrie D, Dunham I (2007). "The landscape of histone modifications across 1% of the human genome in five human cell lines". Genome Res. 17 (6): 691–707. doi:10.1101/gr.5704207. PMC 1891331. PMID 17567990. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b Wang GG, Allis CD, Chi P. (2007). "Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling". Trends Mol Med. 13: 373. PMID 17822959.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ a b Saha A, Wittmeyer J, Cairns BR (2006). "Chromatin remodelling: the industrial revolution of DNA around histones". Nat Rev Mol Cell Biol. 7 (6): 437–47. doi:10.1038/nrm1945. PMID 16723979.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "Saha_2006" was defined multiple times with different content (see the help page).
  13. ^ Hanahan D, Weinberg RA. (2000). "The hallmarks of cancer". Cell. 100: 57. PMID 10647931.
  14. ^ Marks PA, Dokmanovic M (2005). "Histone deacetylase inhibitors: discovery and development as anticancer agents". Expert opinion on investigational drugs. 14 (12): 1497–511. doi:10.1517/13543784.14.12.1497. PMID 16307490.
  15. ^ http://clincancerres.aacrjournals.org/content/8/3/662.full.pdf"Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment" 2002
  16. ^ Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000). "Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation". Proc. Natl. Acad. Sci. U.S.A. 97 (18): 10014–9. doi:10.1073/pnas.180316197. PMC 27656. PMID 10954755. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T (1998). "Retinoblastoma protein recruits histone deacetylase to repress transcription". Nature. 391 (6667): 597–601. doi:10.1038/35404. PMID 9468139. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ Zhang Z, Yamashita H, Toyama T; et al. (2005). "Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*". Breast Cancer Res. Treat. 94 (1): 11–6. doi:10.1007/s10549-005-6001-1. PMID 16172792. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Harvey F. Lodish (2008). Molecular cell biology. St. Martin's Press. pp. 306–. ISBN 978-0-7167-7601-7. Retrieved 26 December 2010.
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