Mediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network
Open Access
- 10 September 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 17 (9), e1009785
- https://doi.org/10.1371/journal.pgen.1009785
Abstract
Dysregulation of cardiac transcription programs has been identified in patients and families with heart failure, as well as those with morphological and functional forms of congenital heart defects. Mediator is a multi-subunit complex that plays a central role in transcription initiation by integrating regulatory signals from gene-specific transcriptional activators to RNA polymerase II (Pol II). Recently, Mediator subunit 30 (MED30), a metazoan specific Mediator subunit, has been associated with Langer-Giedion syndrome (LGS) Type II and Cornelia de Lange syndrome-4 (CDLS4), characterized by several abnormalities including congenital heart defects. A point mutation in MED30 has been identified in mouse and is associated with mitochondrial cardiomyopathy. Very recent structural analyses of Mediator revealed that MED30 localizes to the proximal Tail, anchoring Head and Tail modules, thus potentially influencing stability of the Mediator core. However, in vivo cellular and physiological roles of MED30 in maintaining Mediator core integrity remain to be tested. Here, we report that deletion of MED30 in embryonic or adult cardiomyocytes caused rapid development of cardiac defects and lethality. Importantly, cardiomyocyte specific ablation of MED30 destabilized Mediator core subunits, while the kinase module was preserved, demonstrating an essential role of MED30 in stability of the overall Mediator complex. RNAseq analyses of constitutive cardiomyocyte specific Med30 knockout (cKO) embryonic hearts and inducible cardiomyocyte specific Med30 knockout (icKO) adult cardiomyocytes further revealed critical transcription networks in cardiomyocytes controlled by Mediator. Taken together, our results demonstrated that MED30 is essential for Mediator stability and transcriptional networks in both developing and adult cardiomyocytes. Our results affirm the key role of proximal Tail modular subunits in maintaining core Mediator stability in vivo. MED30 has been associated with congenital heart defects. A point mutation in MED30 has been identified in mouse and is associated with mitochondrial cardiomyopathy. However, the specific role of MED30 in cardiomyocytes remains largely unknown. We found that loss of MED30 resulted in destabilization of the MED core. Our constitutive (cKO) and inducible (icKO) cardiomyocyte specific Med30 knockout mouse models provided us with a unique opportunity to study the role of the intact MED complex in developing heart and adult heart, respectively. We further demonstrated the essential role of MED30 in maintaining specific components of the cardiac gene regulatory network and normal cardiac development and function.Funding Information
- National Heart, Lung, and Blood Institute (HL143210)
- National Heart, Lung, and Blood Institute (HL157115)
- National Heart, Lung, and Blood Institute (R35HL144984)
- National Institute of Child Health and Human Development (1R01HD087417)
- National Institute of Child Health and Human Development (1R01HD094378)
- National Institutes of Health (SIG grant (#S10 OD026929))
This publication has 63 references indexed in Scilit:
- Mediator MED23 plays opposing roles in directing smooth muscle cell and adipocyte differentiationJournal of Bone and Joint Surgery, 2012
- Transcription Factor Pathways and Congenital Heart DiseasePublished by Elsevier BV ,2012
- Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic dietProceedings of the National Academy of Sciences of the United States of America, 2011
- The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulationNature Reviews Genetics, 2010
- Mediator Structural Conservation and Implications for the Regulation MechanismStructure, 2009
- Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature deathHuman Molecular Genetics, 2008
- Comparative genomics supports a deep evolutionary origin for the large, four-module transcriptional mediator complexNucleic Acids Research, 2008
- CHF1/Hey2 Plays a Pivotal Role in Left Ventricular Maturation Through Suppression of Ectopic Atrial Gene ExpressionCirculation Research, 2007
- An essential role of Bmp4 in the atrioventricular septation of the mouse heartGenes & Development, 2003
- A novel mediator between activator proteins and the RNA polymerase II transcription apparatusCell, 1990