Nucleosome Remodeler Exclusion by Histone Deacetylation Enforces Heterochromatic Silencing and Epigenetic Inheritance

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2024 Aug 3

PMID 39096900

Authors

Rakesh Kumar Sahu

Jothy Dhakshnamoorthy

Shweta Jain

Hernan Diego Folco

David Wheeler

Shiv I S Grewal

Affiliations

Soon will be listed here.

Abstract

Heterochromatin enforces transcriptional gene silencing and can be epigenetically inherited, but the underlying mechanisms remain unclear. Here, we show that histone deacetylation, a conserved feature of heterochromatin domains, blocks SWI/SNF subfamily remodelers involved in chromatin unraveling, thereby stabilizing modified nucleosomes that preserve gene silencing. Histone hyperacetylation, resulting from either the loss of histone deacetylase (HDAC) activity or the direct targeting of a histone acetyltransferase to heterochromatin, permits remodeler access, leading to silencing defects. The requirement for HDAC in heterochromatin silencing can be bypassed by impeding SWI/SNF activity. Highlighting the crucial role of remodelers, merely targeting SWI/SNF to heterochromatin, even in cells with functional HDAC, increases nucleosome turnover, causing defective gene silencing and compromised epigenetic inheritance. This study elucidates a fundamental mechanism whereby histone hypoacetylation, maintained by high HDAC levels in heterochromatic regions, ensures stable gene silencing and epigenetic inheritance, providing insights into genome regulatory mechanisms relevant to human diseases.

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