TitleMediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network
AuthorsTan, Changming
Zhu, Siting
Chen, Zee
Liu, Canzhao
Li, Yang E.
Zhu, Mason
Zhang, Zhiyuan
Zhang, Zhiwei
Zhang, Lunfeng
Gu, Yusu
Liang, Zhengyu
Boyer, Thomas G.
Ouyang, Kunfu
Evans, Sylvia M.
Fang, Xi
AffiliationUniv Calif San Diego, Dept Med, San Diego, CA 92103 USA
Cent South Univ, Xiangya Hosp 2, Dept Cardiovasc Surg, Changsha, Hunan, Peoples R China
Peking Univ, Shenzhen Grad Sch, Dept Cardiovasc Surg,Shenzhen Hosp, Sch Chem Biol & Biotechnol,State Key Lab Chem Onc, Shenzhen, Peoples R China
Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA
Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92103 USA
Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA
Southern Med Univ, Zhujiang Hosp, Translat Med Res Ctr, Dept Cardiovasc Med, Guangzhou, Peoples R China
Issue DateSep-2021
AbstractAuthor summary 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. 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.
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