Linker Histone H1.0 Couples Cellular Stiffness to Chromatin Structure [ChIP-seq]

Eukaryotic nuclei encase the genome and differentially package it for the various needs of distinct cell types. Tuning of genome structure and function is accomplished by chromatin binding proteins, which are responsive to cellular stress, determining the transcriptome and phenotype of the cell. We sought to investigate the connection between extracellular stress and chromatin structure to regulate cellular stiffness. We demonstrate that the linker histone H1.0, which compacts nucleosomes into higher order chromatin fibers, controls genome structure and cellular response to stress. Histone H1.0 has privileged expression in tension-responsive fibroblasts across tissue types in mouse and humans, and is necessary and sufficient to mount a myofibroblast phenotype in these cells. Loss of histone H1.0 prevents transforming growth factor beta (TGF-b)-induced fibroblast contraction, proliferation and migration in an isoform-specific manner via inhibition of a transcriptome targeting extracellular matrix molecules. Histone H1.0 is associated with local regulation of gene expression by chromatin fiber compaction and histone acetylation, rendering the nucleus and cell stiffer in response to cytokine stimulation. Knockdown of H1.0 decreased levels of HDAC1 and the chromatin reader BRD4, thereby preventing transcription of a fibrotic gene program. Transient depletion of histone H1.0 in vivo decompacts chromatin and prevents fibrosis in cardiac muscle, lung, and kidney, thereby linking chromatin structure with fibroblast phenotype in response to extracellular stress. Our work identifies an unexpected role of linker histones to sense and respond to cellular stress, directly coupling cellular tension, nuclear organization and gene transcription. ChIP-seq on isolated cardiac fibroblasts, using an antibody against H1.0, FLAG, or H3K27ac.