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 [7]. 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) [7].

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 [3], 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 [2]. Current progress in this field is reviewed by Simó-Riudalbas and Esteller (2015) [9].

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* Key recommended reading is highlighted with an asterisk

Angus SP, Zawistowski JS, Johnson GL. (2018) Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer. Annu Rev Pharmacol Toxicol, 58: 209-229. [PMID:28934561]

* Bates SE. (2020) Epigenetic Therapies for Cancer. N Engl J Med, 383 (7): 650-663. [PMID:32786190]

Bennett RL, Licht JD. (2018) Targeting Epigenetics in Cancer. Annu Rev Pharmacol Toxicol, 58: 187-207. [PMID:28992434]

* Beyer JN, Raniszewski NR, Burslem GM. (2021) Advances and Opportunities in Epigenetic Chemical Biology. Chembiochem, 22 (1): 17-42. [PMID:32786101]

* Carter B, Zhao K. (2021) The epigenetic basis of cellular heterogeneity. Nat Rev Genet, 22 (4): 235-250. [PMID:33244170]

* Hogg SJ, Beavis PA, Dawson MA, Johnstone RW. (2020) Targeting the epigenetic regulation of antitumour immunity. Nat Rev Drug Discov, 19 (11): 776-800. [PMID:32929243]

Lauschke VM, Barragan I, Ingelman-Sundberg M. (2018) Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities. Annu Rev Pharmacol Toxicol, 58: 161-185. [PMID:29029592]

* Oh ES, Petronis A. (2021) Origins of human disease: the chrono-epigenetic perspective. Nat Rev Genet, 22 (8): 533-546. [PMID:33903745]

* Tsai K, Cullen BR. (2020) Epigenetic and epitranscriptomic regulation of viral replication. Nat Rev Microbiol, 18 (10): 559-570. [PMID:32533130]

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, 83 (7): 1316-26. [PMID:25974248]

3. Esteller M. (2008) Epigenetics in cancer. N Engl J Med, 358 (11): 1148-59. [PMID:18337604]

4. Foss FM, Zinzani PL, Vose JM, Gascoyne RD, Rosen ST, Tobinai K. (2011) Peripheral T-cell lymphoma. Blood, 117 (25): 6756-67. [PMID:21493798]

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]