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Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming
Journal article   Open access   Peer reviewed

Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming

Kathryn M Spitler, Jessica M Ponce, Gavin Y Oudit, Duane D Hall and Chad E Grueter
American journal of physiology. Heart and circulatory physiology, Vol.312(4), pp.H768-H780
04/01/2017
DOI: 10.1152/ajpheart.00728.2016
PMCID: PMC5407164
PMID: 28159809
url
https://doi.org/10.1152/ajpheart.00728.2016View
Published (Version of record) Open Access

Abstract

The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function. Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns.
 Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics Up-Regulation Echocardiography Receptors, Estrogen - genetics Heart - embryology Mice, Inbred C57BL Male Ventricular Dysfunction, Left - diagnostic imaging Ventricular Dysfunction, Left - physiopathology Heart - diagnostic imaging Mice, Knockout Pregnancy Stroke Volume Myocardium - enzymology Animals Ventricular Dysfunction, Left - genetics Electron Transport Chain Complex Proteins - metabolism Gene Deletion Ventricular Remodeling - genetics Female Transcription, Genetic Mice Mediator Complex Subunit 1 - genetics PPAR gamma - genetics

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