H1組蛋白可控制表觀遺傳景觀
作者：
小柯機器人發布時間：2020/12/12 19:23:24
美國阿爾伯特·愛因斯坦醫學院Arthur I. Skoultchi研究組取得最新進展。他們提出H1組蛋白通過局部染色質壓縮控制表觀遺傳景觀。這一研究成果發表在2020年12月9日出版的國際學術期刊《自然》雜誌上。
他們顯示H1的局部密度通過促進基因組壓縮來控制阻抑和活躍染色質域的平衡。他們構建了條件性H1基因三敲小鼠品系，並在造血細胞中敲除了H1。T細胞中H1的敲除導致T細胞活化基因的抑制，該過程模仿正常的T細胞活化。正常和H1敲除的CD8 + T細胞中染色質結構的比較表明，H1介導的染色質壓縮主要發生在基因組中的H1水平高於平均水平區域：染色體構象捕獲（Hi-C）B區和用PRC2標記Hi-C A區。
H1化學計量的降低導致H3K27甲基化減少，H3K36甲基化增加，B至A隔室移位以及隔室之間的相互作用頻率增加。在體外，H1促進PRC2介導的H3K27甲基化並抑制NSD2介導的H3K36甲基化。從機理上講，H1通過促進染色質底物的物理壓縮來介導這些相反的作用。他們的結果通過局部控制染色質緊實度、3D基因組組織和表觀遺傳景觀，將H1確立為基因沉默的關鍵調節因子。
研究人員表示，H1接頭組蛋白是最豐富的染色質結合蛋白。體外研究表明，它們與染色質的結合決定了核小體的間隔，並使核小體的陣列摺疊成更緊湊的染色質結構。然而，人們對H1在體內的作用了解甚少。
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