Reprogramming of Cis-Regulatory Networks During Skeletal Muscle Atrophy in Male Mice

Authors

Hongchun Lin
Hui Peng
Yuxiang Sun
Meijun Si
Jiao Wu
Yanlin Wang
Sandhya S Thomas
Zheng Sun
Zhaoyong Hu

Publication Date

10-18-2023

Journal

Nature Communications

DOI

10.1038/s41467-023-42313-3

PMID

37853001

PMCID

PMC10584982

PubMedCentral® Posted Date

10-18-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Male, Animals, Mice, Inbred C57BL, Muscular Atrophy, Muscle, Skeletal, Chromatin, Gene Expression Regulation, Transcription Factors

Abstract

A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic regulatory circuits mediating transitions between myonuclear types. Through comparison of normal and perturbed muscle, we delineated the reprogramming of cis-regulatory networks in response to denervation, described the interplay of promoters/enhancers and target genes. We further unveil a hierarchical structure of transcription factors that delineate a regulatory network in atrophic muscle, identifying ELK4 as a key atrophy-related transcription factor that instigates muscle atrophy through TGF-β1 regulation. This study furnishes a rich genomic resource, essential for decoding the regulatory dynamics of skeletal muscle in both physiological and pathological states.

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