Profiling of histone H1 variants and changes on genome architecture and gene expression upon histone H1 depletion in breast cancer cells

Human somatic cells may contain up to seven members of the histone H1 family contributing to chromatin compaction and its regulation. In breast cancer cells, knock-down (KD) of each H1 variant results in specific gene expression changes. We have previously shown that combined KD of H1.2 and H1.4 (H1 KD) deregulates many genes, promotes the appearance of accessibility sites genome wide and triggers an interferon response via activation of heterochromatic repeats. Here we describe for the first time ChIP-seq profiling of five endogenous H1 variants at the same time, obtaining that H1 variants are differentially distributed at low (H1.2, H1.5, H1.0) and high (H1X, H1.4) GC content regions. Further, we report that H1 KD promotes redistribution of some of the variants and changes on genome architecture. H1 KD decreased topologically associating domain (TAD) border strength as well as its interactions, both inter- and intra-TAD. In addition, many TADs presented a coordinated gene expression response to H1 KD. Up-regulated genes accumulate within TADs with low gene density and high H1.2 content. In conclusion, our data suggests that the equilibrium between distinct histone H1 variants helps maintaining the topological organization of the genome and the proper expression of particular gene programs.