Insights into WDR5: unveiling its functions, regulation, and impact on skeletal muscle.

WD40-repeat-containing protein 5 (WDR5) is a highly conserved multifunctional scaffold protein with a toroidal structure, facilitating interactions with numerous partners through its WDR5-binding motif (WBM) and WDR5-interacting (WIN) sites. It plays a critical role in histone modifications, including H3K4 methylation (H3K4me), histone acetylation, and deacetylation, influencing stem cell maintenance and differentiation. Recent studies highlight its involvement in muscle homeostasis, particularly in skeletal muscle progenitor cells, where it regulates PAX7-driven myogenic factor expression. Additionally, WDR5 governs epigenetic programs in smooth muscle by modulating H3K4me marks on lineage-specific genes. Despite extensive research on its role in cancer and chromatin remodeling, its broader physiological functions remain underexplored. This review examines WDR5's regulatory mechanisms, including its modulation by long non-coding RNAs (lncRNAs), post-translational modifications (PTMs), and microproteins, while emphasizing its relevance to muscle biology. Understanding WDR5's interactome and regulatory networks could provide novel insights into muscle regeneration, stem cell dynamics, and potential therapeutic strategies for muscular disorders and regenerative medicine.