Med13 and Med13L: Critical redundant players in basal cardiac function and gene expression

Abstract

Background

Previous studies have linked mutations in the Mediator complex, specifically Mediator 13 (Med13) and Mediator 13-like (Med13L), with both congenital heart defects and cardiovascular diseases. Med13 and Med13L are mutually exclusive paralogs within the kinase submodule of the Mediator complex that have been shown to have partially redundant functions in embryonic development and transcription, but their combined roles have not been investigated in the adult heart. We investigated the critical yet redundant roles of Med13 and Med13L in adult murine cardiomyocytes for basal cardiac function.

Methods

We generated an inducible Med13 and Med13L cardiomyocyte-specific knockout mouse model to investigate Med13 and Med13L regulation of cardiac function and transcription. We performed RNAseq on mice four weeks after the start of tamoxifen to identify changes in gene expression. Differentially expressed genes were compared across cardiac knockouts of Med13/13L, Med13, Med12, Med1, and Med30 elucidating similar mechanisms of cardiac dysfunction.

Results

Med13/13L knockout resulted in decreased cardiac function leading to lethal heart failure in a median timeframe of 6 weeks from the start of tamoxifen. There is significant gene dysregulation after Med13/13L knockout with similar gene dysregulation of fibrotic pathways and calcium handling across Mediator cardiac knockouts.

Conclusions

Med13 and Med13L function partially redundantly within the heart to maintain basal cardiac function and transcription, as well as redundancies within cardiac phenotypes related to mediator complex disruptions.