The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression.
The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression.
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H3K36me2 甲基转移酶 NSD1 在活性增强子处调节 H3K27ac 以保护基因表达
DOI：
10.1093/nar/gkab473
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发表时间：
2021-06-21
影响因子：
14.9
通讯作者：
Fang D
中科院分区：
文献类型：
--
作者：
Fang Y;Tang Y;Zhang Y;Pan Y;Jia J;Sun Z;Zeng W;Chen J;Yuan Y;Fang D
表观遗传学，特别是组蛋白标记，功能超出DNA序列来调节基因表达。NSD 1催化H3K36me2，其消耗导致基因表达的上调和下调，表明NSD 1与活性和抑制的基因表达相关。已知NSD 1调节基因表达抑制标记H3K27me3的沉积和扩增，以保持基因转录的活跃。然而，NSD 1如何抑制基因表达在很大程度上是未知的。在这里，我们发现，当NSD 1在小鼠胚胎干细胞（mESC）中被敲除时，H3K27 ac的增加与活性增强子处H3K36 me2的减少相关，这与中胚层分化基因相关，导致基因表达升高。在机制上，NSD 1将HDAC 1（H3K27ac的脱乙酰酶）募集到染色质。此外，HDAC1敲除（KO）重现了H3K27ac在活性增强子处的增加，如NSD1耗尽。总之，我们提出NSD 1沉积H3K36me2并在活性增强子处招募HDAC 1作为“保护”，防止活性增强子相关基因的进一步激活。
Epigenetics, especially histone marks, functions beyond the DNA sequences to regulate gene expression. Depletion of NSD1, which catalyzes H3K36me2, leads to both up- and down-regulation of gene expression, indicating NSD1 is associated with both active and repressed gene expression. It's known that NSD1 regulates the deposition and expansion of H3K27me3, a repressive mark for gene expression, to keep active gene transcription. However, how NSD1 functions to repress gene expression is largely unknown. Here, we find that, when NSD1 is knocked out in mouse embryonic stem cells (mESCs), H3K27ac increases correlatively with the decrease of H3K36me2 at active enhancers, which is associated with mesoderm differentiation genes, leading to elevated gene expression. Mechanistically, NSD1 recruits HDAC1, the deacetylase of H3K27ac, to chromatin. Moreover, HDAC1 knockout (KO) recapitulates the increase of H3K27ac at active enhancers as the NSD1 depletion. Together, we propose that NSD1 deposits H3K36me2 and recruits HDAC1 at active enhancers to serve as a ‘safeguard’, preventing further activation of active enhancer-associated genes.
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