Differential regulation during development, aging, and disease implies heart cell specific functions of the Mediator Complex

Transcription directs the heart's development and adaptation to stress signals, and transcriptional dysregulation contributes to developmental disorders, pathological remodeling and heart failure (HF). Stereotypic changes at the mRNA level in the failing heart can be powerful diagnostics, as dysregulation can precede pathological outcomes such as decreased ejection fraction and increased heart size. The Mediator Complex is a general regulator of transcription in all eukaryotic cells; however, unknown subunit- and tissue-specific functions complicate our understanding of Mediator's influence on the cell. Here, we investigated the subunit-specific responses of Mediator throughout cardiac development, aging, and disease at the single cell- and whole ventricle-resolution using single cell RNA-sequencing, bulk RNA-sequencing, qPCR, and assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) datasets from humans and mice. In the developing heart, we discovered that key stages of growth such as ventricle formation were marked with elevated Mediator component expression, which declined during postnatal maturation, but increased again in the aging heart. Heart failure, a heterogenous disease, presented with a global increase in Mediator expression in human and mouse cardiomyocytes. This increased expression was mirrored by increased chromatin accessibility at the promoters of Mediator genes. Collectively, this study reveals the dynamic expression of Mediator subunits throughout the stages of the cardiomyocyte lifecycle and uncovers potential mechanisms by which Mediator is modulated in response to various pathological stimuli.