TY - JOUR
T1 - MED12 regulates a transcriptional network of calcium-handling genes in the heart
AU - Baskin, Kedryn K.
AU - Makarewich, Catherine A.
AU - DeLeon, Susan M.
AU - Ye, Wenduo
AU - Chen, Beibei
AU - Beetz, Nadine
AU - Schrewe, Heinrich
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
N1 - Funding Information:
We thank the members of the ENO laboratory for helpful discussions, Jose Cabrera for help with images, and Wei Tan for echocardiography assistance. We thank John Shelton, James Richardson, the University of Texas Southwestern Histology Core for assistance with histology, and the University of Texas Southwestern Electron Microscopy Core for assistance with EMs. We also thank the University of Texas Southwestern Genomics and Microarray Core for assistance with RNA-Seq. This work was supported by grants from the NIH (HL-077439, HL-130253, DK-099653, AR-067294, and HL-11165), Foundation Leducq Networks of Excellence (14CVD04 to ENO), and the Robert A. Welch Foundation (1-0025 to ENO), NHLBI (1F32HL129674 to CAM), and the American Heart Association (16POST31100009 to KKB).
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/7/20
Y1 - 2017/7/20
N2 - The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes and that MED12 and MEF2 co-occupy promoters of calcium-handling genes. Furthermore, we demonstrated that MED12 enhances MEF2 transcriptional activity and that overexpression of both increases expression of calcium-handling genes in cardiomyocytes. Our data support a role for MED12 as a coordinator of transcription through MEF2 and other transcription factors. We conclude that MED12 is a regulator of a network of calcium-handling genes, consequently mediating contractility in the mammalian heart.
AB - The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes and that MED12 and MEF2 co-occupy promoters of calcium-handling genes. Furthermore, we demonstrated that MED12 enhances MEF2 transcriptional activity and that overexpression of both increases expression of calcium-handling genes in cardiomyocytes. Our data support a role for MED12 as a coordinator of transcription through MEF2 and other transcription factors. We conclude that MED12 is a regulator of a network of calcium-handling genes, consequently mediating contractility in the mammalian heart.
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U2 - 10.1172/jci.insight.91920
DO - 10.1172/jci.insight.91920
M3 - Article
C2 - 28724790
AN - SCOPUS:85061540873
SN - 2379-3708
VL - 2
JO - JCI insight
JF - JCI insight
IS - 14
M1 - e91920
ER -