美国阿尔伯特·爱因斯坦医学院Arthur I. Skoultchi研究组取得最新进展。他们提出H1组蛋白通过局部染色质压缩控制表观遗传景观。这一研究成果发表在2020年12月9日出版的国际学术期刊《自然》杂志上。
他们显示H1的局部密度通过促进基因组压缩来控制阻抑和活跃染色质域的平衡。他们构建了条件性H1基因三敲小鼠品系，并在造血细胞中敲除了H1。T细胞中H1的敲除导致T细胞活化基因的抑制，该过程模仿正常的T细胞活化。正常和H1敲除的CD8 + T细胞中染色质结构的比较表明，H1介导的染色质压缩主要发生在基因组中的H1水平高于平均水平区域：染色体构象捕获（Hi-C）B区和用PRC2标记Hi-C A区。
H1化学计量的降低导致H3K27甲基化减少，H3K36甲基化增加，B至A隔室移位以及隔室之间的相互作用频率增加。在体外，H1促进PRC2介导的H3K27甲基化并抑制NSD2介导的H3K36甲基化。从机理上讲，H1通过促进染色质底物的物理压缩来介导这些相反的作用。他们的结果通过局部控制染色质紧实度、3D基因组组织和表观遗传景观，将H1确立为基因沉默的关键调节因子。
研究人员表示，H1接头组蛋白是最丰富的染色质结合蛋白。体外研究表明，它们与染色质的结合决定了核小体的间隔，并使核小体的阵列折叠成更紧凑的染色质结构。然而，人们对H1在体内的作用了解甚少。
附：英文原文
Title: H1 histones control the epigenetic landscape by local chromatin compaction
Author: Michael A. Willcockson, Sean E. Healton, Cary N. Weiss, Boris A. Bartholdy, Yair Botbol, Laxmi N. Mishra, Dhruv S. Sidhwani, Tommy J. Wilson, Hugo B. Pinto, Maxim I. Maron, Karin A. Skalina, Laura Norwood Toro, Jie Zhao, Chul-Hwan Lee, Harry Hou, Nevin Yusufova, Cem Meydan, Adewola Osunsade, Yael David, Ethel Cesarman, Ari M. Melnick, Simone Sidoli, Benjamin A. Garcia, Winfried Edelmann, Fernando Macian, Arthur I. Skoultchi
Issue&Volume: 2020-12-09
Abstract: H1 linker histones are the most abundant chromatin-binding proteins1. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood2. Here we show that the local density of H1 controls the balance of repressive and active chromatin domains by promoting genomic compaction. We generated a conditional triple-H1-knockout mouse strain and depleted H1 in haematopoietic cells. H1 depletion in T cells leads to de-repression of T cell activation genes, a process that mimics normal T cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T cells reveals that H1-mediated chromatin compaction occurs primarily in regions of the genome containing higher than average levels of H1: the chromosome conformation capture (Hi-C) B compartment and regions of the Hi-C A compartment marked by PRC2. Reduction of H1 stoichiometry leads to decreased H3K27 methylation, increased H3K36 methylation, B-to-A-compartment shifting and an increase in interaction frequency between compartments. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. Our results establish H1 as a critical regulator of gene silencing through localized control of chromatin compaction, 3D genome organization and the epigenetic landscape.
DOI: 10.1038/s41586-020-3032-z
Source: https://www.nature.com/articles/s41586-020-3032-z
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
