Lysine 4 of histone H3.3 is required for embryonic stem cell differentiation, histone enrichment at regulatory regions and transcription accuracy.,Nature Genetics

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Lysine 4 of histone H3.3 is required for embryonic stem cell differentiation, histone enrichment at regulatory regions and transcription accuracy.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-03-05 , DOI: 10.1038/s41588-020-0586-5
Maja Gehre _{1,

2} , Daria Bunina _{1,

3} , Simone Sidoli _{4,

5} , Marlena J Lübke ₁ , Nichole Diaz ₁ , Matteo Trovato _{1,

2} , Benjamin A Garcia ₄ , Judith B Zaugg ₃ , Kyung-Min Noh ₁

Affiliation

Mutations in enzymes that modify histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) have been linked to human disease, yet the role of these residues in mammals is unclear. We mutated K4 or K36 to alanine in the histone variant H3.3 and showed that the K4A mutation in mouse embryonic stem cells (ESCs) impaired differentiation and induced widespread gene expression changes. K4A resulted in substantial H3.3 depletion, especially at ESC promoters; it was accompanied by reduced remodeler binding and increased RNA polymerase II (Pol II) activity. Regulatory regions depleted of H3.3K4A showed histone modification alterations and changes in enhancer activity that correlated with gene expression. In contrast, the K36A mutation did not alter H3.3 deposition and affected gene expression at the later stages of differentiation. Thus, H3K4 is required for nucleosome deposition, histone turnover and chromatin remodeler binding at regulatory regions, where tight regulation of Pol II activity is necessary for proper ESC differentiation.

中文翻译：

组蛋白 H3.3 的赖氨酸 4 是胚胎干细胞分化、调控区域组蛋白富集和转录准确性所必需的。

在赖氨酸 4 (H3K4) 或赖氨酸 36 (H3K36) 修饰组蛋白 H3 的酶发生突变与人类疾病有关，但这些残基在哺乳动物中的作用尚不清楚。我们将组蛋白变体 H3.3 中的 K4 或 K36 突变为丙氨酸，并表明小鼠胚胎干细胞 (ESC) 中的 K4A 突变损害了分化并诱导了广泛的基因表达变化。K4A 导致大量 H3.3 耗尽，尤其是在 ESC 启动子处；它伴随着重塑剂结合减少和 RNA 聚合酶 II (Pol II) 活性增加。耗尽 H3.3K4A 的调节区域显示组蛋白修饰改变和与基因表达相关的增强子活性变化。相反，K36A 突变不改变 H3.3 沉积并影响分化后期的基因表达。因此，

更新日期：2020-04-24

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