title: Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice.
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.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Next Generation Sequencing Core Facility, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schipma
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Varsha
authors.initials: V
authors.lastname: Shete
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Barger
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
authors.affiliation: Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Bayar
authors.initials: B
authors.lastname: Thimmapaya
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D004734:Energy Metabolism; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D005865:Gestational Age; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056913:Mediator Complex Subunit 1 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: C529218:CACNA1S protein, mouse; D015820:Cadherins; D020746:Calcium Channels, L-Type; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D047492:Peroxisome Proliferator-Activated Receptors; D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; C070896:M-cadherin; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517273:Pde1C protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse