HIRA stabilizes skeletal muscle lineage identity

Area of Science:

• Epigenetics
• Cellular Biology
• Muscle Stem Cell Biology

Background:

• Epigenetic mechanisms controlling cell identity and preventing alternative cell fates are not fully understood.
• The role of histone chaperones in maintaining adult cellular lineages requires further investigation.

Purpose of the Study:

• To investigate the role of the histone chaperone HIRA in maintaining skeletal muscle cellular identity.
• To elucidate the epigenetic mechanisms by which HIRA regulates muscle stem cell function and regeneration.

Main Methods:

• Conditional ablation of HIRA in adult mouse myogenic cells and muscle stem cells.
• Transcriptional profiling and chromatin analysis (H3.3 deposition, H3K27ac, H3K4me3).
• Analysis of gene expression from alternative lineages.

Main Results:

• HIRA ablation in myogenic cells caused significant transcriptional changes, impacting skeletal muscle identity.
• Conditional HIRA deficiency in muscle stem cells led to impaired regeneration and self-renewal, resulting in tissue repair failure.
• Hira-deficient cells showed reduced H3.3 and H3K27ac at muscle gene regulatory regions and ectopic expression of alternative lineage genes due to increased H3K4me3.

Conclusions:

• HIRA is essential for sustaining the chromatin landscape that defines muscle cell lineage identity.
• HIRA incorporates histone variant H3.3 at muscle gene regulatory regions, thereby maintaining skeletal muscle identity.
• HIRA prevents the expression of alternative lineage genes, ensuring proper tissue homeostasis.