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HIRA stabilizes skeletal muscle lineage identity

Author

Listed:
  • Joana Esteves de Lima

    (Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB)

  • Reem Bou Akar

    (Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB)

  • Léo Machado

    (Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB)

  • Yuefeng Li

    (University of Ottawa
    Ottawa Hospital Research Institute)

  • Bernadette Drayton-Libotte

    (Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB)

  • F. Jeffrey Dilworth

    (University of Ottawa
    Ottawa Hospital Research Institute)

  • Frédéric Relaix

    (Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB)

Abstract

The epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.

Suggested Citation

  • Joana Esteves de Lima & Reem Bou Akar & Léo Machado & Yuefeng Li & Bernadette Drayton-Libotte & F. Jeffrey Dilworth & Frédéric Relaix, 2021. "HIRA stabilizes skeletal muscle lineage identity," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23775-9
    DOI: 10.1038/s41467-021-23775-9
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