Hu Shuaishuai, Chapski Douglas J, Gehred Natalie D, Kimball Todd H, Gromova Tatiana, Flores Angelina, Rowat Amy C, Chen Junjie, Packard René R Sevag, Olszewski Emily, Davis Jennifer, Rau Christoph D, McKinsey Timothy A, Rosa-Garrido Manuel, Vondriska Thomas M
Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA USA.
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA USA.
Nat Cardiovasc Res. 2024;3(4):441-459. doi: 10.1038/s44161-024-00460-w. Epub 2024 Apr 10.
Tuning of genome structure and function is accomplished by chromatin-binding proteins, which determine the transcriptome and phenotype of the cell. Here we investigate how communication between extracellular stress and chromatin structure may regulate cellular mechanical behaviors. We demonstrate that histone H1.0, which compacts nucleosomes into higher-order chromatin fibers, controls genome organization and cellular stress response. We show that histone H1.0 has privileged expression in fibroblasts across tissue types and that its expression is necessary and sufficient to induce myofibroblast activation. Depletion of histone H1.0 prevents cytokine-induced fibroblast contraction, proliferation and migration via inhibition of a transcriptome comprising extracellular matrix, cytoskeletal and contractile genes, through a process that involves locus-specific H3K27 acetylation. Transient depletion of histone H1.0 in vivo prevents fibrosis in cardiac muscle. These findings identify an unexpected role of linker histones to orchestrate cellular mechanical behaviors, directly coupling force generation, nuclear organization and gene transcription.
染色质结合蛋白可实现基因组结构和功能的调控，这些蛋白决定了细胞的转录组和表型。在此，我们研究细胞外应激与染色质结构之间的通讯如何调节细胞的力学行为。我们证明，组蛋白H1.0可将核小体压缩成高阶染色质纤维，控制基因组组织和细胞应激反应。我们发现，组蛋白H1.0在跨组织类型的成纤维细胞中具有优先表达，其表达对于诱导肌成纤维细胞活化是必要且充分的。组蛋白H1.0的缺失可通过抑制包括细胞外基质、细胞骨架和收缩基因的转录组，通过涉及位点特异性H3K27乙酰化的过程，来阻止细胞因子诱导的成纤维细胞收缩、增殖和迁移。体内组蛋白H1.0的短暂缺失可预防心肌纤维化。这些发现确定了连接组蛋白在协调细胞力学行为方面的意外作用，直接将力的产生、核组织和基因转录联系起来。
