德国欧洲分子生物学实验室Kyung-Min Noh研究团队在研究中取得进展。他们发现组蛋白H3.3的赖氨酸4（K4）是胚胎干细胞分化、调节区域组蛋白富集和转录准确性所必需的。2020年3月5日出版的《自然-遗传学》发表了这项成果。

他们在组蛋白变体H3.3中将K4或K36突变为丙氨酸（K4A和K36A），并表明小鼠胚胎干细胞（ESC）中的K4A突变会损害分化并引起广泛的基因表达变化。K4A导致大量的H3.3消耗，尤其是在ESC启动子处；它伴随着减少的重塑子结合和RNA聚合酶II（Pol II）活性增加。调控区域H3.3 K4A的消耗表明组蛋白修饰的变化和与基因表达相关的增强子活性的变化。相反，K36A突变不会改变H3.3的分布，并不会影响分化后期的基因表达。因此，H3K4是核糖体分布、组蛋白更新和染色质重塑子结合在调控区域所必需的，调控区域的Pol II活性的严格调控对于适当的ESC分化是必需的。

据了解，修饰组蛋白H3赖氨酸4（H3K4）或赖氨酸36（H3K36）位点的酶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。

附：英文原文

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

Author: Maja Gehre, Daria Bunina, Simone Sidoli, Marlena J. Lbke, Nichole Diaz, Matteo Trovato, Benjamin A. Garcia, Judith B. Zaugg, Kyung-Min Noh

Issue&Volume: 2020-03-05

Abstract: 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.

DOI: 10.1038/s41588-020-0586-5

Source: https://www.nature.com/articles/s41588-020-0586-5