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

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.

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

“…As Mediator function is closely associated with energy utilization and homeostasis (22,24,(39)(40)(41), it is not entirely unexpected that overexpression of Cdk8 results in a large enrichment of downregulated mitochondrial-based metabolic genes and pathways (Figures 6 and 7). In fact, we see considerable overlap between the RNA-seq results presented here (885 of 1,160 genes expressed >1.5-fold, r 2 = 0.61) and those from cardiac deletion of the core Mediator subunit Med1 (Med1cKO) that we recently reported (24). It is intriguing that 94% of the shared genes between presymptomatic Cdk8-transgenic and advanced dilated Med1cKO ventricles have the same directionality in terms of upregulation or downregulation.…”

“…This submodule regulates gene expression through its dynamic association with the Mediator core complex and through its Cdk8 activity (19)(20)(21). We recently reported the novel observation that cardiac Med13 functions to regulate whole-body energy homeostasis (22,23) and that Med1 is essential in postnatal and adult cardiomyocytes (24); however, the function of Mediator kinase activity has yet to be determined. Knockdown and overexpression studies in other systems have shown that Cdk8 can impart both activating and repressive effects on transcription in celland gene-specific contexts (25)(26)(27)(28).…”

MED12 regulates a transcriptional network of calcium-handling genes in the heart

“…It was recently reported by two independent groups that cardiac-specific deletion of Med1 leads to severe DCM and premature death in mice. Although many calcium-handling genes were downregulated in the Med1 -/-heart, they were measured after the onset of DCM, which has been associated with decreased calcium-handling gene expression, as discussed above (49,50).…”

Investigating the roles of cyclin C in the mammalian heart

“…Cardiac-specific deletion of Med1 in mice results in dilated cardiomyopathy, decreased cardiac function and lethality 59 . Mutations in Med23 and Med25 have been linked to congenital heart disease in clinical studies 60,61 . In addition, Med14 mutants give rise to heart defects in zebrafish 62 .…”

“…Gene expression was analyzed using the ΔΔCT method and relative expression was normalized to Rpl7l1. Sequences for the primers are as listed in previous studies 60,65 .…”