Dataset Information

Integrated omics approaches to characterize a nuclear receptor corepressor-associated histone deacetylase in mouse skeletal muscle.

ABSTRACT: Nuclear receptors regulate gene expression by differentially binding to coactivators or corepressors in a ligand-dependent manner, which further recruits a set of epigenome-modifying enzymes that remodel chromatin conformation. Histone acetylation is a major epigenomic change controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC3 is the only HDAC that confers the enzymatic activity to the complexes nucleated by nuclear receptor corepressors NCoR and SMRT. To address the metabolic function of HDAC3, we have deleted it specifically in mouse skeletal muscles. We have performed the following omics profiling in skeletal muscles of these mice: (1) RNA-seq profiling of total RNA; (2) Global nuclear run-on (GRO-seq) analysis of nascent RNAs; (3) Chromatin immuno-precipitation (ChIP-seq) of HDAC3 at both early evening and early morning; (4) proteomics profiling with mass spectrometry; (5) snap-shot metabolomics profiling of water-soluble metabolites at the basal condition; (6) snap-shot metabolomics profiling of lipid species at the basal condition; (7) kinetic fluxomics analysis of glucose utilization using 13C6-glucose In vivo during treadmill running exercise. These approaches have provided several novel insights into how nuclear receptors regulate circadian rhythm of skeletal muscle fuel metabolism, which has been published elsewhere. Here we present the original datasets and technical details during the execution, analysis, and interpretation of these omics studies.

SUBMITTER: Gong Y

PROVIDER: S-EPMC5702591 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Integrated omics approaches to characterize a nuclear receptor corepressor-associated histone deacetylase in mouse skeletal muscle.

Gong Yingyun Y Cao Rui R Ding Guolian G Hong Sungguan S Zhou Wenjun W Lu Wenyun W Damle Manashree M Fang Bin B Wang Chuhan C CC Qian Justin J Lie Natasha N Lanzillotta Cristina C Rabinowitz Joshua D JD Sun Zheng Z

Molecular and cellular endocrinology 20170526

Nuclear receptors regulate gene expression by differentially binding to coactivators or corepressors in a ligand-dependent manner, which further recruits a set of epigenome-modifying enzymes that remodel chromatin conformation. Histone acetylation is a major epigenomic change controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC3 is the only HDAC that confers the enzymatic activity to the complexes nucleated by nuclear receptor corepressors NCoR and SMRT. To addr ...[more]

PMID: 28554803

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Project description:ObjectivePhysical exercise training is associated with increased glucose uptake in skeletal muscle and improved glycemic control. HDAC5, a class IIa histone deacetylase, has been shown to regulate transcription of the insulin-responsive glucose transporter GLUT4 in cultured muscle cells. In this study, we analyzed the contribution of HDAC5 to the transcriptional network in muscle and the beneficial effect of muscle contraction and regular exercise on glucose metabolism.MethodsHDAC5 knockout mice (KO) and wild-type (WT) littermates were trained for 8 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. Hdac5-deficient skeletal muscle and cultured Hdac5-knockdown (KD) C2C12 myotubes were utilized for studies of gene expression and glucose metabolism. Chromatin immunoprecipitation (ChIP) studies were conducted to analyze Il6 promoter activity using H3K9ac and HDAC5 antibodies.ResultsGlobal transcriptome analysis of Hdac5 KO gastrocnemius muscle demonstrated activation of the IL-6 signaling pathway. Accordingly, knockdown of Hdac5 in C2C12 myotubes led to higher expression and secretion of IL-6 with enhanced insulin-stimulated activation of AKT that was reversed by Il6 knockdown. Moreover, Hdac5-deficient myotubes exhibited enhanced glucose uptake, glycogen synthesis, and elevated expression levels of the glucose transporter GLUT4. Transcription of Il6 was further enhanced by electrical pulse stimulation in Hdac5-deficient C2C12 myotubes. ChIP identified a ∼1 kb fragment of the Il6 promoter that interacts with HDAC5 and demonstrated increased activation-associated histone marker AcH3K9 in Hdac5-deficient muscle cells. Exercise intervention of HDAC5 KO mice resulted in improved systemic glucose tolerance as compared to WT controls.ConclusionsWe identified HDAC5 as a negative epigenetic regulator of IL-6 synthesis and release in skeletal muscle. HDAC5 may exert beneficial effects through two different mechanisms, transcriptional control of genes required for glucose disposal and utilization, and HDAC5-dependent IL-6 signaling cross-talk to improve glucose uptake in muscle in response to exercise.

Dataset Information

Integrated omics approaches to characterize a nuclear receptor corepressor-associated histone deacetylase in mouse skeletal muscle.

Publications

Integrated omics approaches to characterize a nuclear receptor corepressor-associated histone deacetylase in mouse skeletal muscle.

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