Hoxa10 is a functional positional memory that governs stem cell function in adult skeletal muscle

Skeletal muscle is contractile tissue distributed throughout the body with functionally heterogeneous properties that may relate to region-specific pathophysiology of muscle diseases. Recent studies revealed that muscle stem cells (satellite cells) are a functional heterogeneous population in different muscles, dependent not only on fiber-types but also on embryonic origin. Homeobox (Hox) genes are key regulators of the embryonic body plan. Here, we showed that Hox-A cluster genes are robustly maintained in adult muscles and their associated satellite cells of both mice and humans in a body region-specific manner, whose distribution almost recapitulates their embryonic origin. The region-specific expression of Hox genes was linked to DNA hypermethylation status of Hox-A locus. Importantly, Hox gene expression is a functional memory; Hoxa10 inactivation in satellite cells led to genomic instability and mitotic catastrophe, resulting in a decline in the regionally specific regenerative ability of muscles in mice, even though Hox paralogs are known to be often functionally redundant. Thus, our results demonstrate that the topographic Hox gene expression profile could be a geotagging molecular signature that reflects the anatomical location and embryonic history of resident muscle stem cells, potentially contributing to regionally specific regulations of adult skeletal muscles. Overall design: Genomic DNAs were extracted from MAS and TA muscle tissues and plated satellite cells of adult mice. Libraries for whole-genome bisulfite sequencing was prepared as described in Miura F et al (2019), NAR, 47, e85