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Dynamic enhancers control skeletal muscle identity and reprogramming.

Krithika Ramachandran1, Madhavi D Senagolage1, Meredith A Sommars1

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Skeletal muscle adaptation involves distinct epigenomic programs. Exercise and PGC1α activation remodel muscle enhancers differently, revealing unique regulatory networks for muscle identity and response to stimuli.

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Area of Science:

  • Muscle physiology and epigenetics
  • Skeletal muscle adaptation and regulation

Background:

  • The epigenomic basis of skeletal muscle identity and adaptation to exercise is not well understood.
  • Skeletal muscles comprise fibers with diverse metabolic activities and contractility, which change with chronic exercise.

Purpose of the Study:

  • To dissect cis-regulatory networks in skeletal muscles in vivo.
  • To understand the epigenomic basis of muscle identity and adaptation.
  • To compare the epigenomic changes induced by exercise versus PGC1α overexpression.

Main Methods:

  • Chromatin immunoprecipitation sequencing (ChIP-seq) for H3K4me2 and H3K27ac.
  • Transposase-accessible chromatin profiling (ATAC-seq).
  • Integrative analysis of regulatory regions and gene expression data.

Main Results:

  • In vivo enhancers specify muscles based on myofiber composition, differing from cultured myotube enhancers.
  • Voluntary wheel running and PGC1α overexpression induce distinct epigenomic changes: exercise causes hypoacetylation, while PGC1α causes hyperacetylation.
  • Both stimuli activate MEF2 and ERR signaling for oxidative metabolism genes, but exercise additionally involves RXR, JUN, and SIX factors.

Conclusions:

  • Defines unique enhancer repertoires for skeletal muscles in vivo.
  • Reveals divergent epigenomic programs driven by exercise or PGC1α.
  • Demonstrates that these programs direct partially convergent transcriptional networks for muscle adaptation.