Depletion of H1.3 in AML cells prompts redistribution of H1.2, causing chromatin remodeling and cell cycle deregulation [ChIP-Seq]

Linker histone H1 variants play critical, yet distinct, roles in chromatin organization and gene regulation. However, very little is known about their specificity in cancer cells. In this study, we investigated the specificity of the H1.3 variant in acute myeloid leukaemia (AML) cells. Through chromatin mapping and transcriptomic analyses, we revealed that H1.3 was specifically enriched in regions with a high GC content and co-localized with the repressive mark H3K27me3, supporting its role in chromatin compaction and transcriptional repression. Knockout of H1.3 induced specific changes in gene expression profiles and chromatin dynamics, characterized by the relocalization of H1.2, which was redistributed from its usual chromatin regions to the freed H1.3 regions. Consequently, locus-specific chromatin alterations associated with interferon-related signalling pathways and cell cycle deregulation were observed. Our findings emphasized an important and locus-specific function of H1.3 in AML cells. Overall, our study revealed a mechanistic connection between H1 variant imbalance, activation of the immune response, and regulation of the cell cycle, with implications for our understanding of epigenetic regulation in cancer cells.