Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming.
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-specificMed1knockout 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.NEW & NOTEWORTHYDisruption 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.
Division of Cardiovascular Medicine, Department of Internal Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa; and.
Kathryn M
KM
Spitler
Division of Cardiovascular Medicine, Department of Internal Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa; and.
Jessica M
JM
Ponce
Mazankowski Alberta Heart Institute Canada Research Chair in Heart Failure, Division of Cardiology, Walter Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada.
Gavin Y
GY
Oudit
Division of Cardiovascular Medicine, Department of Internal Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa; and.
Duane D
DD
Hall
Division of Cardiovascular Medicine, Department of Internal Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa; and chad-grueter@uiowa.edu.
Chad E
CE
Grueter
D000818:Animals; D004452:Echocardiography; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006321:Heart / Q000000981:diagnostic imaging / Q000196:embryology; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D047495:PPAR gamma / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000235:genetics; D013318:Stroke Volume; D014158:Transcription, Genetic; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000235:genetics*; D000097983:ERRalpha Estrogen-Related Receptor
D045222:Electron Transport Chain Complex Proteins; D056913:Mediator Complex Subunit 1; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C538856:Med1 protein, mouse; C485290:Ppargc1a protein, mouse
cardiovascular disease; mediator complex; metabolism; transcription