A fastMyhsuper enhancer dictates adult muscle fiber phenotype through competitive interactions with the fastMyhgenes

Summary The contractile properties of adult myofibers are shaped by their Myosin heavy chain (MYH) isoform content. We identify by snATAC-seq a 42kb super-enhancer (SE) at the locus regrouping the fast Myh (f Myh ) genes. By 4C-seq we show that active f Myh promoters interact with the SE by DNA looping, leading to the activation of a single promoter per nucleus. A rainbow mouse transgenic model of the locus including the SE recapitulates the endogenous spatio-temporal expression of adult f Myh genes. In situ deletion of the SE by CRISPR/Cas9 editing demonstrates its major role in the control of associated f Myh genes, and deletion of two f Myh genes at the locus reveals an active competition of the promoters for the shared SE. Last, by disrupting the organization of f Myh , we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.