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Histone H1 depletion in cancer cells promotes changes on genome architecture related to gene expression deregulation

AuthorsSerna, Núria; Salinas, M.; Mugianesi, F.; Martí-Renom M.; Jordan, Albert
Issue Date17-Dec-2019
CitationVII Jornada de Bioinformática y Genómica, de la Societat Catalana de Biologia (2019)
AbstractHistone H1 binds to the linker DNA at the nucleosome, participating in the formation of higher-order chromatin structures. Human somatic cells may contain up to seven members of the histone H1 family contributing to the regulation of nuclear processes, apparently with certain subtype specificities. We have previously shown that in T47D breast cancer cells, the combined knock-down of H1.2 and H1.4 subtypes (multi-H1 KD) has a strong deleterious effect, deregulates many genes, promotes the appearance of accessibility sites genome-wide and triggers an interferon response via activation of heterochromatic repeats. Now, through the integration of chromatin immunoprecipitation followed by sequencing (ChIP-Seq), RNA sequencing (RNA-Seq) and high-throughput chromosome conformation capture (Hi-C) techniques, we aim to elucidate the biological role of different H1 subtypes in the interplay between genome architecture and gene expression. Our results support that histone H1 variants are differentially distributed in topologically associating domains (TADs) and A/B compartments. For instance, TADs located within compact and GC-poor genomic regions were characterized by a high H1.2/H1X content ratio and overlapped with the B compartment of the 3D genome. Multi-H1 KD increased TAD border definition and intra-TAD contacts, while decreased inter-TAD interactions. Moreover, TADs enriched in histone H1.2 showed major transitions from B to A compartment and changes in interactions. Multi-H1 depletion also promoted genes deregulation in 40% of total TADs. Specifically, up-regulated genes accumulated within TADs presenting high H1.2/H1X ratios and low gene richness, while the opposite occurs in TADs containing down-regulated genes. Within affected TADs, the frequency of deregulated genes compared to total gene count was higher in those with a high H1.2/H1X ratio. In conclusion, our data suggest that the equilibrium between distinct histone H1 variants is involved in maintaining the topological organization of the genome and the proper expression of particular gene programs.
DescriptionResumen del trabajo presentado en las VII Jornada de Bioinformática y Genómica, de la Societat Catalana de Biologia, celebradas en Barcelona (España), el 17 de diciembre de 2019
Appears in Collections:(IBMB) Comunicaciones congresos
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