Fig. 1.

Epigenetic regulation of chromatin accessibility and gene expression. Nucleosomes (blue cylinders) are formed by DNA wrapped around a histone octamer which allows DNA to be condensed into chromatin and finally chromosomes. Epigenetic mechanisms dynamically tune chromatin accessibility especially at cis regulatory elements of gene expression. Post-translational modification of N- and C-terminal histone “tails” regulate nucleosome stability, chromatin compaction and serve as docking sites for proteins that recognize epigenetic marks such as bromodomain proteins (BRD). Histone methyltransferases (HMTs) catalyze the transfer of a methyl group (Me) onto histone tails from donor S-adenyl methionine while this mark is removed by histone demethylases (HDM). Similarly, histone acetyltransferases (HATs) transfer an acetyl group (Ac) from acetyl coenzyme A to histone lysine residues which weakens histone interaction with DNA to increase chromatin accessibility. Histone deacetylases (HDACs) remove the acetyl mark from histones, decreasing chromatin accessibility and subduing gene expression. Chromatin remodelers such as SWI/SNF mobilize and reposition nucleosomes. DNA methyltransferases (DNMT) methylate CpG islands near transcription start sites that inhibit gene expression by impeding transcription factor binding to DNA. Epigenetic inhibitors (white ovals) have been developed to potentially restore a normal cellular epigenetic state to tumor cells. EZH2i, such as tazemetostat, specifically inhibit the gene suppressive methylation of histone H3 by PRC2. HDACi such as entinostat or vorinostat inhibit histone deacetylation to reactivate gene expression. Inhibitors of bromodomain and extra terminal domain proteins (BETi) such as JQ1 or BMS-986158 suppress aberrant gene expression driven by increased BRD activity in cancer cells. DNMT inhibitors (DNMTi) such as azacytidine promote DNA hypomethylation and reactivate expression of tumor suppressor genes