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Chromatin modifying enzymes, and other chromatin-modifying proteins, fall into three broad categories: writers, readers and erasers. The function of these proteins is to dynamically maintain cell identity and regulate processes such as differentiation, development, proliferation and genome integrity via recognition of specific 'marks' (covalent post-translational modifications) on histone proteins and DNA . In normal cells, tissues and organs, precise co-ordination of these proteins ensures expression of only those genes required to specify phenotype or which are required at specific times, for specific functions. Chromatin modifications allow DNA modifications not coded by the DNA sequence to be passed on through the genome and underlies heritable phenomena such as X chromosome inactivation, aging, heterochromatin formation, reprogramming, and gene silencing (epigenetic control).
To date at least eight distinct types of modifications are found on histones. These include small covalent modifications such as acetylation, methylation, and phosphorylation, the attachment of larger modifiers such as ubiquitination or sumoylation, and ADP ribosylation, proline isomerization and deimination. Chromatin modifications and the functions they regulate in cells are reviewed by Kouzarides (2007) .
Writer proteins include the histone methyltransferases, histone acetyltransferases, some kinases and ubiquitin ligases.
Readers include proteins which contain methyl-lysine-recognition motifs such as bromodomains, chromodomains, tudor domains, PHD zinc fingers, PWWP domains and MBT domains.
Erasers include the histone demethylases and histone deacetylases (HDACs and sirtuins).
Dysregulated epigenetic control can be associated with human diseases such as cancer , where a wide variety of cellular and protein abberations are known to perturb chromatin structure, gene transcription and ultimately cellular pathways [1,8]. Due to the reversible nature of epigenetic modifications, chromatin regulators are very tractable targets for drug discovery and the development of novel therapeutics. Indeed, small molecule inhibitors of writers (e.g. azacitidine and decitabine target the DNA methyltransferases DNMT1 and DNMT3 for the treatment of myelodysplastic syndromes [5,10]) and erasers (e.g. the HDAC inhibitors vorinostat, romidepsin and belinostat for the treatment of T-cell lymphomas [4,6]) are already being used in the clinic. The search for the next generation of compounds with improved specificity against chromatin-associated proteins is an area of intense basic and clinical research . Current progress in this field is reviewed by Simó-Riudalbas and Esteller (2015) .
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1. Baylin SB, Jones PA. (2011) A decade of exploring the cancer epigenome - biological and translational implications. Nat. Rev. Cancer, 11 (10): 726-34. [PMID:21941284]
2. Cabaye A, Nguyen KT, Liu L, Pande V, Schapira M. (2015) Structural diversity of the epigenetics pocketome. Proteins, [Epub ahead of print]. [PMID:25974248]
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5. Garcia-Manero G, Fenaux P. (2011) Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J. Clin. Oncol., 29 (5): 516-23. [PMID:21220589]
6. Khan O, La Thangue NB. (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol. Cell Biol., 90 (1): 85-94. [PMID:22124371]
7. Kouzarides T. (2007) Chromatin modifications and their function. Cell, 128 (4): 693-705. [PMID:17320507]
8. Simó-Riudalbas L, Esteller M. (2014) Cancer genomics identifies disrupted epigenetic genes. Hum. Genet., 133 (6): 713-25. [PMID:24104525]
9. Simó-Riudalbas L, Esteller M. (2015) Targeting the histone orthography of cancer: drugs for writers, erasers and readers. Br. J. Pharmacol., 172 (11): 2716-32. [PMID:25039449]
10. Wells RA, Leber B, Zhu NY, Storring JM. (2014) Optimizing outcomes with azacitidine: recommendations from Canadian centres of excellence. Curr Oncol, 21 (1): 44-50. [PMID:24523604]
Database page citation:
Chromatin modifying enzymes. Accessed on 28/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=865.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol. 172: 6024-6109.