Regulation of cardiac transcription by thyroid hormone and Med13

Thyroid hormone (TH) is a key regulator of transcriptional homeostasis in the heart. While hypothyroidism is known to result in adverse cardiac effects, the molecular mechanisms that modulate TH signaling are not completely understood. Mediator is a multiprotein complex that coordinates signal-dependent transcription factors with the basal transcriptional machinery to regulate gene expression. Mediator complex protein, Med13, represses numerous thyroid receptor (TR) response genes in the heart. Further, cardiac-specific overexpression of Med13 in mice that were treated with propylthiouracil (PTU), an inhibitor of the biosynthesis of the active TH, triiodothyronine (T3), resulted in resistance to PTU-dependent decreases in cardiac contractility. Therefore, these studies aimed to determine if Med13 is necessary for the cardiac response to hypothyroidism. Here we demonstrate that Med13 expression is induced in the hearts of mice with hypothyroidism. To elucidate the role of Med13 in regulating gene transcription in response to TH signaling in cardiac tissue, we utilized an unbiased RNA sequencing approach to define the TH-dependent alterations in gene expression in wild-type mice or those with a cardiac-specific deletion in Med13 (Med13cKO). Mice were fed a diet of PTU to induce a hypothyroid state or normal chow for either 4 or 16 weeks, and an additional group of mice on a PTU diet were treated acutely with T3 to re-establish a euthyroid state. Echocardiography revealed that wild-type mice had a decreased heart rate in response to PTU with a trend toward a reduced cardiac ejection fraction. Notably, cardiomyocyte-specific deletion of Med13 exacerbated cardiac dysfunction. Collectively, these studies reveal cardiac transcriptional pathways regulated in response to hypothyroidism and re-establishment of a euthyroid state and define molecular pathways that are regulated by Med13 in response to TH signaling.