Analysis of the transcriptomic changes of myoblasts lacking Hira [RNA-seq]

The epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates are poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications consistent with a major role in maintaining skeletal muscle cellular identity. Conditional ablation of HIRA in muscle stem cells of adult mice compromised their capacity to regenerate and self-renew, leading to tissue repair failure. Epigenetic analysis of Hira-deficient cells showed a drastic reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. By contrast, genes from alternative lineages were ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, HIRA sustains the epigenetic landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes. Examining the transcriptomic changes in proliferating myoblasts lacking Hira