Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
PLoS Genet. 2012;8(8):e1002879. doi: 10.1371/journal.pgen.1002879. Epub 2012 Aug 30.
Linker histones are essential components of chromatin, but the distributions and functions of many during cellular differentiation are not well understood. Here, we show that H1.5 binds to genic and intergenic regions, forming blocks of enrichment, in differentiated human cells from all three embryonic germ layers but not in embryonic stem cells. In differentiated cells, H1.5, but not H1.3, binds preferentially to genes that encode membrane and membrane-related proteins. Strikingly, 37% of H1.5 target genes belong to gene family clusters, groups of homologous genes that are located in proximity to each other on chromosomes. H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction. Depletion of H1.5 results in loss of SIRT1 and H3K9me2, increased chromatin accessibility, deregulation of gene expression, and decreased cell growth. Our data reveal for the first time a specific and novel function for linker histone subtype H1.5 in maintenance of condensed chromatin at defined gene families in differentiated human cells.
连接组蛋白是染色质的重要组成部分，但在细胞分化过程中，许多连接组蛋白的分布和功能还不是很清楚。在这里，我们发现在来自三个胚胎胚层的分化人类细胞中，但不在胚胎干细胞中，H1.5 结合到基因和基因间区域，形成富集的块，而 H1.3 则没有。在分化的细胞中，H1.5 而不是 H1.3 优先结合编码膜和膜相关蛋白的基因。引人注目的是，37%的 H1.5 靶基因属于基因家族簇，即位于染色体上彼此靠近的同源基因群。H1.5 结合与基因抑制有关，并且需要 SIRT1 结合、H3K9me2 富集和染色质紧缩。H1.5 的耗竭导致 SIRT1 和 H3K9me2 的丢失、染色质可及性增加、基因表达失调和细胞生长减少。我们的数据首次揭示了连接组蛋白亚型 H1.5 在维持分化人类细胞中特定基因家族的浓缩染色质方面的特定和新功能。
