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

Abstract

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 (fMyh) genes. By 4C-seq we show that active fMyh 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 fMyh genes. In situ deletion of the SE by CRISPR/Cas9 editing demonstrates its major role in the control of associated fMyh genes, and deletion of two fMyh genes at the locus reveals an active competition of the promoters for the shared SE. Last, by disrupting the organization of fMyh, we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.

H3K18 lactylation marks tissue-specific active enhancers

“…S1D), which is also strongly H3K18la marked. Myhas, also known as Linc-Myh, is adjacent to the fMyh SE and suppresses slow-type Myh gene expression while stimulating fast-type Myh gene expression (Myh1, Myh2, Myh4) through enhancer-promoter looping [48,49]. It is therefore plausible that Myh1 gene expression is regulated in MT through Myhas and activation and hyperlactylation of its enhancer.…”