Coordinated changes in gene expression, H1 variant distribution and genome 3D conformation in response to H1 depletion

Abstract

Up to seven members of the histone H1 family may contribute to chromatin compaction and its regulation in human somatic cells. In breast cancer cells, knock-down of multiple H1 variants deregulates many genes, promotes the appearance of genome-wide accessibility sites and triggers an interferon response via activation of heterochromatic repeats. However, how these changes in the expression profile relate to the re-distribution of H1 variants as well as to genome conformational changes have not been yet studied. Here, we combined ChIP-seq of five endogenous H1 variants with Chromosome Conformation Capture analysis in wild-type and H1.2/H1.4 knock-down T47D cells. The results indicate that H1 variants coexist in the genome in two large groups depending on the local GC content and that their distribution is robust with respect to H1 depletion. Despite the small changes in H1 variants distribution, knock-down of H1 translated into more isolated but de-compacted chromatin structures at the scale of topologically associating domains (TADs). Such changes in TAD structure correlated with a coordinated gene expression response of their resident genes. This is the first report describing simultaneous profiling of five endogenous H1 variants and giving functional evidence of genome topology alterations upon H1 depletion in human cancer cells.

Histone H1.0 Couples Cellular Mechanical Behaviors to Chromatin Structure

“…Unlike transcription factors or some modified core nucleosome histones, the distribution of linker histone H1 across the genome is fairly ubiquitous (Serna-Pujol et al, 2022; Teif et al, 2020). To reveal regions of targeted regulation by histone H1.0, we performed ChIP-seq for histone H1.0 (Figure S4B) and investigated regions of relative depletion as described (Ito-Ishida et al, 2018).…”

“…These findings highlight the central role of histone stoichiometry in controlling normal development and tissue homeostasis (Fyodorov et al, 2018; Zhou et al, 2015). In cancer cells, altering histone H1 levels substantially reorganized global chromatin structure, decompacting topologically associating domains (Serna-Pujol et al, 2022) and shifting the genome to a more relaxed state (Yusufova et al, 2021).…”

The Protective Effect of Pumpkin and Fermented Whey Mixture against AFB1 and OTA Immune Toxicity In Vitro. A Transcriptomic Approach

“…Herein, the decreased H1.4 expression was observed, which was associated with a strong induction of IFN response in vitro (Figure 2). [ 58 ]…”

Nucleosome reorganisation in breast cancer tissues

“…External datasets. Raw data from ChIP-seq of histone H1 variants in T47D breast cancer cell line reported in (27) was obtained from GEO entry GSE156036 and mapped using Bowtie to genome hg19, considering only uniquely mapped reads with up to 1 mismatch. The hg19 coordinates of A and B chromatin compartments in MCF-7 cells reported in (28) were kindly provided by the author.…”

“…DMR regions defined above (29) were also extended by 1,000 bp on both sides. Regions enriched with H1X were defined based on MACS2 peak calling with default parameters using ChIP-seq of H1X in the T47D breast cancer cell line reported in (27), resulting in 33,337 peaks which were extended by 1,000 bp on both sides. Coordinates of chromatin A-compartments in human genome assembly hg38 defined based on Hi-C in MCF-7 cells were kindly provided by the author of the original publication (28) and converted to hg19 using LiftOver utility of the UCSC Genome Browser.…”