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.
Highlights
Cardiac morphogenesis and maintenance of cardiac physiology require complex and wellorchestrated transcription programs [1,2,3]
Our constitutive and inducible 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 Mediator subunit 30 (MED30) in maintaining specific components of the cardiac gene regulatory network and normal cardiac development and function
Summary
Cardiac morphogenesis and maintenance of cardiac physiology require complex and wellorchestrated transcription programs [1,2,3]. Mediator is an evolutionarily conserved protein complex that plays a central role in transcription initiation by integrating regulatory signals from gene-specific transcriptional activators to RNA polymerase II (Pol II) [8,9,10,11,12]. Previous structural analysis of yeast Mediator has provided an understanding of the conserved core of the complex and its interaction with Pol II but failed to reveal the structure of the Tail module that contains the majority of subunits that interact with transcriptional factors([18]. The newly revealed structure suggests that the subunits of the proximal Tail potentially influence the stability and conformation of the core Mediator [19,20,21,22,23]. These important new insights into Mediator structure are suggestive of cellular and MED30 is essential for MED stability physiological roles of the Mediator subunits in the proximal Tail, that remain to be functionally tested
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