Cardiomyocyte‐specific deletion of Med13 & Med13L results in dysregulated gene expression and lethal systolic heart failure

Abstract

The Mediator co‐activation complex is an important component in RNA Pol II‐dependent gene expression that functions to integrate intracellular signals, allowing for optimized cellular response to (patho)physiological states. The Mediator kinase submodule functions to fine‐tune these molecular transitions. The kinase submodule consists of four proteins, including Med13, Med12, Cdk8, and Cyclin C. Also involved is the Med13 paralog, Med13‐like (Med13L), which is both mutually exclusive in the submodule and partially redundant. Approximately 22% of reported human mutations in MED13 or MED13L have congenital heart defects often resulting in dysregulated cardiac metabolism and aberrant cardiovascular physiology. Therefore, we hypothesize that the acute loss of Med13 and Med13L in cardiomyocytes results in disrupted Mediator kinase submodule formation leading to altered gene expression and subsequent pathogenesis of heart failure. To investigate this, we created a Tamoxifen‐inducible cardiomyocyte‐specific Med13/Med13L double knockout mouse model and treated mice for two weeks with Tamoxifen beginning at eight‐weeks‐old. Following treatment, mice had significant progressive decreased ejection fraction consistent with severe heart failure. Survival studies demonstrate rapid mortality—50% of Med13/Med13L cardiac knockout mice die within four weeks. Post‐mortem analysis showed increased heart weight and heart‐weight‐to‐body‐weight ratio as well as gross histology consistent with dilated hypertrophy. To begin elucidating the mechanistic processes underlying these findings, mRNA sequencing was performed prior to observed declines in cardiac function and showed that cardiac stress response pathways were differentially expressed. Specifically, the Wnt‐β‐catenin pathway was activated, while basal transcription was unchanged. Taken together, Med13 and Med13L are critical for normal Mediator‐regulated RNA Pol II‐dependent transcription and subsequent cardiac physiology. Therefore, disruptions cause significant cardiac dysfunction and death as sequelae of heart failure.