Abstract
How a single genome can give rise to distinct cell types remains a fundamental question in biology. Mammals are able to specify and maintain hundreds of cell fates by selectively activating unique subsets of their genome. This is achieved, in part, by enhancers—genetic elements that can increase transcription of both nearby and distal genes. Enhancers can be identified by their unique chromatin signature, including transcription factor binding and the enrichment of specific histone post-translational modifications, histone variants, and chromatin-associated cofactors. How each of these chromatin features contributes to enhancer function remains an area of intense study. In this review, we provide an overview of enhancer-associated chromatin states, and the proteins and enzymes involved in their establishment. We discuss recent insights into the effects of the enhancer chromatin state on ongoing transcription versus their role in the establishment of new transcription programmes, such as those that occur developmentally. Finally, we highlight the role of enhancer chromatin in new conceptual advances in gene regulation such as condensate formation.
Highlights
Enhancers are short cis-regulatory elements that facilitate transcription of nearby genes
Nucleosomes at enhancers are enriched with the H2A.Z and H3.3 histone variants which are deposited at these regions by dedicated histone chaperones and chromatin remodelling complexes [20,21,23,31,32], it must be noted that both H2A.Z and H3.3 play roles at heterochromatic regions under certain circumstances [20,33,34,35,36,37]
This observation could be explained by several mechanisms, for example: (i) H3.3S31ph may recruit a p300 activator or prevent the binding of an inhibitor at enhancers; (ii) H3.3S31ph allosterically stimulates p300 activity, possibly by forming a stable interaction in a manner analogous to stimulation by enhancer RNAs (eRNAs); or (iii) phosphorylated H3.3 may be a more permissive substrate which, upon acetylation, allows p300 to remain chromatin-bound via its bromodomain to acetylate adjacent canonical histones
Summary
Enhancers are short (typically 100 bp to 1 kb) cis-regulatory elements that facilitate transcription of nearby genes. Studies over the years have demonstrated that genes receive regulatory input from multiple enhancers whose usage is regulated in space and time over the course of development [6]. These elements drive spatio-temporal changes in gene expression resulting in morphological divergence among closely related species [7,8,9]. Excellent reviews have covered determinants of regulatory element activity [17], how enhancer–promoter interactions are established and maintained [12], and transcription factor function at enhancers [18]. We discuss how enhancer chromatin may play a role in novel theories of transcription such as the role of biomolecular condensates in gene regulation
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