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. 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.

异染色质（Heterochromatin）可介导转录基因沉默，并能以表观遗传方式传递，但其背后的分子机制长期以来尚未阐明。本研究证实，作为异染色质结构域保守特征的组蛋白去乙酰化，可阻断参与染色质解聚的SWI/SNF亚家族染色质重塑因子，进而稳定修饰后的核小体，维持基因沉默状态。当组蛋白去乙酰化酶（histone deacetylase, HDAC）缺失，或组蛋白乙酰转移酶被直接靶向至异染色质区域，导致组蛋白高度乙酰化时，重塑因子便可获得染色质访问权限，进而引发基因沉默缺陷。通过抑制SWI/SNF的活性，可绕过异染色质沉默过程对HDAC的依赖。值得注意的是，即便在HDAC功能完整的细胞中，仅需将SWI/SNF靶向至异染色质区域，即可提升核小体周转效率，引发基因沉默异常与表观遗传传递受损，这进一步凸显了染色质重塑因子的关键作用。本研究阐明了一项核心机制：异染色质区域内高表达的HDAC可维持组蛋白低乙酰化状态，从而保障稳定的基因沉默与表观遗传传递，为与人类疾病相关的基因组调控研究提供了重要见解。本研究附带裂殖酵母中Snf22、Snf21蛋白及三甲基化赖氨酸9组蛋白H3的染色质免疫沉淀测序（Chromatin Immunoprecipitation DNA-sequencing, ChIP-seq）数据，每项实验均提供了Input对照与免疫沉淀样本。