Disrupting the DREAM complex enables proliferation of adult human pancreatic beta cells

Resistance to regeneration of insulin-producing pancreatic ?? cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human ?? cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and ?? cell transcriptomic databases seeking to understand why ?? cells in insulinomas proliferate, while normal ?? cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human ?? cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human ?? cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.