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P300 and CBP are essential for skeletal muscle homeostasis, contractile function and survival

ABSTRACT: Reversible ε-amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function is unknown. In this study, we investigated the role of the related acetyltransferases p300 and CBP in skeletal muscle transcriptional homeostasis and physiology in adult mice. These data reveal that p300 and CBP are required for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle, and ultimately, organism survival.

ORGANISM(S): Mus musculus

PROVIDER: GSE141857 | GEO | 2019/12/12

REPOSITORIES: GEO

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p300 and CBP are essential for skeletal muscle homeostasis, contractile function and survival

Project description:Reversible epsilon-amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function remain enigmatic. In this study, we investigated the role of the homologous acetyltransferases p300 and CBP in skeletal muscle transcriptional homeostasis and physiology in adult mice. Mice with skeletal muscle-specific and inducible knockout of p300 and/or CBP were generated by crossing mice with a tamoxifen-inducible Cre recombinase expressed under the human alpha-skeletal actin (HSA) promoter with mice harboring LoxP sites flanking exon 9 of both the Ep300 and Crebbp genes. Knockout was induced at 13-15 weeks of age via oral gavage of tamoxifen. We demonstrate that loss of both p300 and CBP in adult mouse skeletal muscle severely impairs contractile function and results in lethality within one week – a phenotype that is reversed by the presence of a single allele of either p300 or CBP. The loss of muscle function in p300/CBP double knockout mice is paralleled by substantial transcriptional alterations in gene networks central to skeletal muscle contraction and structural integrity. Changes in protein expression patterns, determined by 10-plex TMT labeling, were linked to impaired muscle function also manifest within days (WT mice were compared to day 3 and day 5 knock out mice). Together, these data reveal the requirement of p300 and CBP for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle, and ultimately, organism survival. By extension, modulating p300/CBP function holds promise for the treatment of disorders characterized by impaired contractile function in humans.

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Project description:The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators; however, their acetylation targets, site-specific acetylation kinetics, and function in proteome regulation are incompletely understood. We combined quantitative proteomics with novel CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to show that CBP/p300 acetylates thousands of sites, including signature histone sites, as well as a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Kinetic analysis identified a subset of CBP/p300-regulated sites with very rapid (<30min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions, as well as for understanding the impact of small molecule inhibitors targeting its catalytic and bromodomain activities.

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