Differential Epigenetic Modifications of Histones at the Myosin Heavy Chain Genes in Fast and Slow Skeletal Muscle Fibers and in Response to Muscle Unloading

Abstract

In order to delineate the relationship between epigenetic modifications and myosin heavy chain (MHC) gene regulation, we examined histone modifications of the four MHC genes (I, IIa, IIx, IIb) in fast vs. slow fiber‐type rat skeletal muscle, and in a model of muscle unloading, which causes a coordinated shift from slow to fast MHC gene expression in the soleus (sol). We used chromatin immunoprecipitation (ChIP) to examine acetylation of histone H3 (AcH3) and histone H3 lysine 4 trimethylation (H3K4me3). We report that both AcH3 and H3K4me3 correlate with the transcriptional activity, assessed via pre‐ and mRNA, of each of the MHC genes in both fast plantaris and slow sol. Likewise, during dynamic MHC remodeling of sol with unloading, the slow (I, IIa) to fast (IIx, IIb) transition in mRNA parallels alterations in histone modifications (p<0.05). Thus, I and IIa MHC genes become de‐acetylated when their transcription is down‐regulated, while induction of the fast IIx and IIb MHCs occurs in conjunction with enhanced acetylation at those genes. H3K4me3 is similarly altered. These observations demonstrate the feasibility of using the ChIP assay to understand the native chromatin environment in adult skeletal muscle, and also suggest that the transcriptional state of MHC genes are sensitive to histone modifications both in different muscle fiber‐types and in response to altered loading states. Supported by NIH AR30346‐25