Transcriptional coactivator MED15 is required for beta cell maturation

Mediator, a co-regulator required for RNA pol II activity, interacts with tissue-specific transcription factors to regulate development and maintain homeostasis. We sought to understand whether Mediator subunit MED15 acts as a node that controls tissue-specific gene expression, using pancreatic insulin-producing β-cell maturation as a model. We found Med15 to be expressed during mouse pancreatic organogenesis and β-cell maturation; moreover, islets from human T2D donors feature reduced MED15 expression. Loss of Med15 in mouse β-cells caused defects in maturation without affecting β-cell mass or insulin expression. ChIP-seq and co-immunoprecipitation analyses determined that Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 to regulate key β-cell maturation genes. Human embryonic stem cell derived β-like cells, genetically engineered to express high levels of MED15, had increased maturation markers and improved insulin secretion. We provide the first evidence of the importance of Mediator in β-cell maturation and demonstrate an additional layer of control that tunes transcription factor function.