Chromatin remodeling

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 Sha, K. and Boyer, L. A. The chromatin signature of pluripotent cells (May 31, 2009), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.45.1.





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

Covalent histone-modifying complexes[edit]

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.[2]

Known modifications[edit]

Well characterized modifications to histones include:[3]





Histone code hypothesis[edit]





Type of
H3K4 H3K9 H3K14 H3K27 H3K79 H4K20 H2BK5
acetylation activation[11] activation[11]

ATP-dependent chromatin remodeling[edit]



Known chromatin remodeling complexes[edit]


Specific functions[edit]

  • 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.[12]


In normal biological processes[edit]





Cancer genomics[edit]


Therapeutic intervention[edit]

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.[18][19] 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.[20] 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.[21]

Started pivotal phase II clinical trials


Other disease syndromes[edit]

  • CHARGEsyndrome, an autosomal dominant disorder, has been linked recently to haploinsufﬁciency of CHD7, which encodes the CHD family ATPase CHD7.[23]

See also[edit]

  1. Epigenetics
  2. Histone
  3. Nucleosomes
  4. Chromatin
  5. Histone acetyltransferase
  6. Transcription factors

References for further reading[edit]


  1. ^ Teif VB, Rippe K. (2009). "Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities.". Nucleic Acids Res. 37 (17): 5641–55. doi:10.1093/nar/gkp610. PMC 2761276. PMID 19625488. 
  2. ^ Wang GG, Allis CD, Chi P. (2007). "Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling.". Trends Mol Med. 13 (9): 363–72. doi:10.1016/j.molmed.2007.07.003. PMID 17822958. 
  3. ^ Strahl B, Allis C (2000). "The language of covalent histone modifications". Nature 403 (6765): 41–5. doi:10.1038/47412. PMID 10638745. 
  4. ^ 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. 
  5. ^ Hublitz, Philip; Albert, Mareike; Peters, Antoine (28 April 2009). "Mechanisms of Transcriptional Repression by Histone Lysine Methylation". The International Journal of Developmental Biology (Basel) 10 (1387): 335–354. ISSN 1696-3547. 
  6. ^ 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. 
  12. ^ a b Wang GG, Allis CD, Chi P. (2007). "Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling.". Trends Mol Med. 13 (9): 373–80. doi:10.1016/j.molmed.2007.07.004. PMID 17822959. 
  13. ^ 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. 
  14. ^ Hanahan D, Weinberg RA. (2000). "The hallmarks of cancer.". Cell 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9. PMID 10647931. 
  15. ^ Versteege, I; Sévenet, N; Lange, J; Rousseau-Merck, MF; Ambros, P; Handgretinger, R; Aurias, A; Delattre, O (Jul 9, 1998). "Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer.". Nature 394 (6689): 203–6. doi:10.1038/28212. PMID 9671307. 
  16. ^ Shain, AH; Pollack, JR (2013). "The spectrum of SWI/SNF mutations, ubiquitous in human cancers.". PLoS ONE 8 (1): e55119. doi:10.1371/journal.pone.0055119. PMC 3552954. PMID 23355908. 
  17. ^ Wolffe AP. (2001). "Chromatin remodeling: why it is important in cancer.". Oncogene 20 (24): 2988–90. doi:10.1038/sj.onc.1204322. PMID 11420713. 
  18. ^ 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. 
  19. ^"Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment" 2002
  20. ^ Richon VM, Sandhoff TW, Rifkind RA, Marks PA (August 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. 
  21. ^ Zhang Z, Yamashita H, Toyama T, et al. (November 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. 
  22. ^ Dowden J, Hong W, Parry RV, Pike RA, Ward SG (April 2010). "Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases". Bioorg. Med. Chem. Lett. 20 (7): 2103–5. doi:10.1016/j.bmcl.2010.02.069. PMID 20219369. 
  23. ^ Clapier CR, Cairns BR. (2009). "The biology of chromatin remodeling complexes.". Annu Rev Biochem. 78: 273–304. doi:10.1146/annurev.biochem.77.062706.153223. PMID 19355820. 

External links[edit]