异染色质强制转录基因沉默,并且可以是表观遗传的,但潜在的机制仍不清楚。这里,我们显示组蛋白去乙酰化,异染色质结构域的保守特征,阻断参与染色质分解的SWI/SNF亚家族重塑,从而稳定保留基因沉默的修饰的核小体。组蛋白高乙酰化,由于组蛋白脱乙酰酶(HDAC)活性的丧失或组蛋白乙酰转移酶直接靶向异染色质,允许改造者进入,导致沉默缺陷。可以通过阻碍SWI/SNF活性来绕过在异染色质沉默中对HDAC的要求。突出改造者的关键作用,仅将SWI/SNF靶向异染色质,即使在具有功能性HDAC的细胞中,增加核小体周转,导致有缺陷的基因沉默和受损的表观遗传。这项研究阐明了组蛋白低乙酰化的基本机制,由异色区的高HDAC水平维持,确保稳定的基因沉默和表观遗传,提供与人类疾病相关的基因组调控机制的见解。
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.