Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers.
Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers.
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DOI：
10.1101/gr.192229.115
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发表时间：
2015-09
期刊：
影响因子：
7
通讯作者：
Bustin M
中科院分区：
文献类型：
--
作者：
Deng T;Zhu ZI;Zhang S;Postnikov Y;Huang D;Horsch M;Furusawa T;Beckers J;Rozman J;Klingenspor M;Amarie O;Graw J;Rathkolb B;Wolf E;Adler T;Busch DH;Gailus-Durner V;Fuchs H;Hrabě de Angelis M;van der Velde A;Tessarollo L;Ovcherenko I;Landsman D;Bustin M
DNA酶I超敏位点（DHS）是含有调控DNA（如增强子和启动子）的染色质区域的标志;然而，影响这些位点建立和维持的因素尚未完全了解。我们现在表明，HMGN 1和HMGN 2，核小体结合蛋白，在脊椎动物细胞中普遍表达，协同维持DHS景观的小鼠胚胎成纤维细胞（MEFs）。这些HMGN变体之一的丢失导致剩余变体结合的补偿性增加。对Hmgn 1 −/−、Hmgn 2 −/−和Hmgn 1 −/−n2−/− MEFs中DHS的全基因组定位显示，两者的缺失（而非单一HMGN变体）导致DHS景观的显著重塑，特别是在H3 K4 me 1和H3 K27 ac标记的增强子区域。HMGN变体的缺失影响MEFs中应激反应基因的诱导表达，几种小鼠组织的转录谱，并导致在仅缺乏一种变体的小鼠中未观察到的表型改变。我们得出结论，HMGN变体与染色质的补偿性结合维持了DHS景观和转录保真度，并且是保留野生型表型所必需的。我们的研究提供了深入了解机制，保持在染色质中的调节位点和核小体结合的建筑蛋白之间的功能补偿。
DNase I hypersensitive sites (DHSs) are a hallmark of chromatin regions containing regulatory DNA such as enhancers and promoters; however, the factors affecting the establishment and maintenance of these sites are not fully understood. We now show that HMGN1 and HMGN2, nucleosome-binding proteins that are ubiquitously expressed in vertebrate cells, maintain the DHS landscape of mouse embryonic fibroblasts (MEFs) synergistically. Loss of one of these HMGN variants led to a compensatory increase of binding of the remaining variant. Genome-wide mapping of the DHSs in Hmgn1−/−, Hmgn2−/−, and Hmgn1−/−n2−/− MEFs reveals that loss of both, but not a single HMGN variant, leads to significant remodeling of the DHS landscape, especially at enhancer regions marked by H3K4me1 and H3K27ac. Loss of HMGN variants affects the induced expression of stress-responsive genes in MEFs, the transcription profiles of several mouse tissues, and leads to altered phenotypes that are not seen in mice lacking only one variant. We conclude that the compensatory binding of HMGN variants to chromatin maintains the DHS landscape, and the transcription fidelity and is necessary to retain wild-type phenotypes. Our study provides insight into mechanisms that maintain regulatory sites in chromatin and into functional compensation among nucleosome binding architectural proteins.