Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice.

Yuzhi Jia,Matthew J Schipma,Hsiang-Chun Chang,Philip M Barger,Bayar Thimmapaya,Ning Liu,Janardan K Reddy,Tatsuya Sato,Yashpal S Kanwar,Varsha Shete,Navin Viswakarma,Edward B Thorp,Yi-Jun Zhu,Hossein Ardehali,Jing Liu

doi:10.1371/journal.pone.0160755

Yuzhi Jia, Matthew J Schipma + Show 13 more

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https://doi.org/10.1371/journal.pone.0160755

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Abstract

Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1-/-) during late gestational and early postnatal development by intercrossing Med1fl/fl mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1-/- mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1-/- heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1-/-), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1-/- studies described above are highly reproducible in TmcsMed1-/- mouse heart. Collectively, these observations suggest that Med1 plays a critical role in the maintenance of heart function impacting on multiple metabolic, compensatory and reparative pathways with a likely therapeutic potential in the management of heart failure.

Highlights

Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a major component of eukaryotic transcription machinery [1,2]
Mediator subunit 1 (Med1), a major subunit of the Mediator, plays a central role in nuclear receptor mediated gene expression including peroxisome proliferator-activated receptor (PPAR)α-induced activation of an array of genes related to energy homeostasis in liver and ligand bound thyroid hormone receptor induced regulation of a large number of genes involved in protein, fat and carbohydrate metabolism [9,10,11,12]
The mechanisms involved in the control of tissue specific gene expression are complex in which a number of transcription factors, coactivators, and epigenetic factors coordinate at the promoter of each gene to initiate transcription

Summary

Introduction

An evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a major component of eukaryotic transcription machinery [1,2]. The major cause of death of Med null mouse embryos at E11.5 was likely to be due to severe cardiac failure because of non-compaction of the ventricular myocardium and the resultant ventricular dilatation [16]. These poorly developed hearts showed large pericardial effusion associated with a dilated blood filled ventricle. A large number of inherited mutations were shown to contribute to different forms of cardiomyopathy including dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive and hypertrophic cardiomyopathy [17] These mutations do not map to any of the known members of the Mediator subunits. Our studies for the first time provide evidence for a critical role for Med in heart function impacting on multiple pathways related to cardiac contraction, oxidative phosphorylation and energy metabolism

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