A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism

Amoasii, Leonela; Holland, William L.; Baskin, Kedryn K.; Pearson, Mackenzie; Burgess, Shawn C.; Nelson, Benjamin R.; Bassel‐Duby, Rhonda; Olson, Eric N.

doi:10.1101/gad.273128.115

Cited by 34 publications

(39 citation statements)

References 55 publications

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“…For example, as mentioned above, MED12 positively regulates Wnt target genes in HEK293 cells and in Drosophila (41,58), but in Caenorhabditis elegans (C. elegans), MED12 seems to be an inhibitor of Wnt/β-catenin-mediated gene expression (62,63). We previously reported opposing metabolic functions of MED13 in cardiac and skeletal muscle, yet another example of cell-specific functions of Mediator subunits (64). Additionally, loss of Med23 facilitates smooth muscle cell differentiation but represses adipocyte differentiation by regulating different sets of genes in a cell-dependent manner (65).…”

Section: Med12mentioning

confidence: 92%

MED12 regulates a transcriptional network of calcium-handling genes in the heart

Baskin¹,

Makarewich²,

DeLeon³

et al. 2017

JCI Insight

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IntroductionHeart failure is the leading cause of death in the Western world (1). Defective calcium (Ca 2+ ) cycling, such as decreased Ca 2+ uptake in the sarcoplasmic reticulum (SR) or SR calcium leak occurs in failing hearts (2, 3), and genetic mutations in calcium-handling genes cause arrhythmias and dilated cardiomyopathy (DCM) (4). Altered expression of calcium-handling genes perturbs contractility (5-9), but relatively little is known about how the expression of these genes is coordinated in the heart.Mediator is a multiprotein complex of about 30 subunits that form the core and kinase submodules (10, 11). The kinase submodule, containing MED12, MED13, CDK8, and Cyclin C (12), can repress transcription through allosteric inhibition of RNA Pol II binding to the core submodule (13) but can also activate transcription by promoting Pol II recruitment to target genes via specific transcription factors (14). We previously demonstrated that cardiac MED13 regulates systemic energy homeostasis through signaling to extracardiac tissues (15,16), but the roles of the other kinase components in the heart have not been investigated.MED12, a component of the Mediator kinase submodule, is encoded on the X chromosome, and missense mutations are associated with a variety of X-linked disorders (17)(18)(19). Developmental signaling pathways and transcription factors converge on MED12, which acts as a transcriptional hub required to coordinate development (20)(21)(22)(23). Deletion of Med12 in Drosophila decreases expression of sonic hedgehog target genes and leads to defects in eye development (20), and mutations in Med12 in zebrafish disrupt SOX-mediated transcription during endoderm development (22). MED12 is also required for neuron development through its regulation of TBX2B in zebrafish (23). Med12 hypomorphic mutant mice die in utero due to various developmental defects (24, 25), but the function of MED12 in the heart has not yet been investigated.The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes an...

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Section: Med12mentioning

confidence: 92%

MED12 regulates a transcriptional network of calcium-handling genes in the heart

Baskin¹,

Makarewich²,

DeLeon³

et al. 2017

JCI Insight

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“…For example, Mediator complex subunit activity, such as MED13, within muscle plays an evolutionarily conserved role in the regulation of lipid accumulation in various tissues [15, 16]. Muscle-specific PGC1-α transcription factor activity can drive changes in the metabolic function of white fat through regulation of the myokine irisin [12].…”

Section: Introductionmentioning

confidence: 99%

Muscle Directs Diurnal Energy Homeostasis through a Myokine-Dependent Hormone Module in Drosophila

Zhao

Karpac

2017

Current Biology

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Summary Inter-tissue communication is critical to control organismal energy homeostasis in response to temporal changes in feeding and activity or external challenges. Muscle is emerging as a key mediator of this homeostatic control through consumption of lipids, carbohydrates, and amino acids, as well as governing systemic signaling networks. However, it remains less clear how energy substrate usage tissues, such as muscle, communicate with energy substrate storage tissues in order to adapt with diurnal changes in energy supply and demand. Using Drosophila, we show here that muscle plays a crucial physiological role in promoting systemic synthesis and accumulation of lipids in fat storage tissues, which subsequently impacts diurnal changes in circulating lipid levels. Our data reveal that the metabolic transcription factor Foxo governs expression of the cytokine Unpaired 2 (Upd2) in skeletal muscle, which acts as a myokine to control glucagon-like adipokinetic hormone (AKH) secretion from specialized neuroendocrine cells. Circulating AKH levels, in turn, regulate lipid homeostasis in fat body/adipose and the intestine. Our data also reveal that this novel myokine-dependent hormone module is critical to maintain diurnal rhythms in circulating lipids. This tissue cross-talk provides a putative mechanism that allows muscle to integrate autonomous energy demand with systemic energy storage and turnover. Together, these findings reveal a diurnal inter-tissue signaling network between muscle and fat-storage tissues that constitutes an ancestral mechanism governing systemic energy homeostasis.

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“…Numerous members of the NR family are sensors of metabolic status that respond to dietary signals and metabolites, and are responsible for metabolic adaptation at the cell, organ, and whole organismal level (Fig. 3) (Ito and Roeder 2001; Ge et al 2002, 2008; Huss 2004; Smith and Muscat 2005; Yang et al 2006; Wang et al 2009; Chen et al 2010; Grontved et al 2010; Krebs et al 2011; Rana et al 2011; Grueter et al 2012; Zhao et al 2012; Baskin et al 2014; Chu et al 2014; Jia et al 2014, 2016; Lee et al 2014; Amoasii et al 2016). Mediator complex subunits have been shown to interact strongly with numerous NRs in a ligand-dependent manner, and to interact with transcription factors to regulate a variety of metabolic processes.…”

Section: The Mediator Complexmentioning

confidence: 99%

Control of Muscle Metabolism by the Mediator Complex

Amoasii

Olson

Bassel‐Duby

2017

Cold Spring Harb Perspect Med

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Exercise represents an energetic challenge to whole-body homeostasis. In skeletal muscle, exercise activates a variety of signaling pathways that culminate in the nucleus to regulate genes involved in metabolism and contractility; however, much remains to be learned about the transcriptional effectors of exercise. Mediator is a multiprotein complex that links signal-dependent transcription factors and other transcriptional regulators with the basal transcriptional machinery, thereby serving as a transcriptional “hub.” In this article, we discuss recent studies highlighting the role of Mediator subunits in metabolic regulation and glucose metabolism, as well as exercise responsiveness. Elucidation of the roles of Mediator subunits in metabolic control has revealed new mechanisms and molecular targets for the modulation of metabolism and metabolic disorders.

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A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism

Cited by 34 publications

References 55 publications

MED12 regulates a transcriptional network of calcium-handling genes in the heart

MED12 regulates a transcriptional network of calcium-handling genes in the heart

Muscle Directs Diurnal Energy Homeostasis through a Myokine-Dependent Hormone Module in Drosophila

Control of Muscle Metabolism by the Mediator Complex

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