Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Nucleic Acids Res. 2021 Jun 21;49(11):6281-6295. doi: 10.1093/nar/gkab473.
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.
表观遗传学，尤其是组蛋白标记，超越了 DNA 序列的功能，调节基因表达。催化 H3K36me2 的 NSD1 的缺失会导致基因表达的上调和下调，表明 NSD1 与活跃和抑制基因表达都有关联。众所周知，NSD1 调节 H3K27me3 的沉积和扩展，H3K27me3 是基因表达的抑制标记，以保持活跃的基因转录。然而，NSD1 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 NSD1 在小鼠胚胎干细胞（mESCs）中被敲除时，H3K27ac 会在活性增强子处与 H3K36me2 的减少相关联增加，这与中胚层分化基因有关，导致基因表达升高。从机制上讲，NSD1 将组蛋白去乙酰化酶 HDAC1 募集到染色质上。此外，HDAC1 的敲除（KO）会模拟 NSD1 缺失时活性增强子处 H3K27ac 的增加。总之，我们提出 NSD1 在活性增强子上沉积 H3K36me2 并募集 HDAC1，充当“保护者”，防止与活性增强子相关的基因进一步激活。
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