Nucleosome remodeler exclusion by histone deacetylation enforces heterochromatic silencing and epigenetic inheritance

Heterochromatin enforces transcriptional gene silencing and can be epigenetically inherited, but the underlying mechanism has remained 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 a histone deacetylase (HDAC) or the direct targeting of histone acetyltransferase to heterochromatin, permits remodeler access, leading to silencing defects.The requirement for HDAC in heterochromatin silencing can be bypassedby 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 significant insights into genome regulation relevant to human diseases. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for the proteins Snf22, Snf21, and the lysine 9 trimethylated histone H3 in fission yeast. Input control and immunoprecipitation samples are provided for each experiment.