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 ß-cell maturation as a model. We found Med15 to be expressed during mouse pancreatic organogenesis and ß-cell maturation; moreover, islets from human T2D donors feature reduced MED15 expression. Loss of Med15 in mouse ß-cells caused defects in maturation without affecting ß-cell mass or insulin expression. ChIP-seq and co-immunoprecipitation analyses determined that Med15 binds ß-cell transcription factors Nkx6-1 and NeuroD1 to regulate key ß-cell maturation genes. Human embryonic stem cell derived ß-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 ß-cell maturation and demonstrate an additional layer of control that tunes transcription factor function. Overall design: 1)ChIP-seq on mouse MIN6 cells and islets 2)RNAseq on control and beta cell-specific Med15 knockout islets