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

Abstract

Resistance to regeneration of insulin-producing pancreatic β 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 β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β 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 β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

Key Elements of Cellular Senescence Involve Transcriptional Repression of Mitotic and DNA Repair Genes Through the p53-p16/pRB-E2F-DREAM Complex

“…Repression of FOXM1 during aging is known to trigger dysfunctional mitotic machinery and contribute to aneuploidy-driven senescence, while cyclic FOXM1 expression delayed senescence and alleviated aging phenotypes in progeroid mice 52,53 . Recently, disturbing DREAM complex with small molecule kinase DYRK1A inhibitor have shown to improve proliferation of adult human pancreatic β cells 54 . In agreement with previous studies, we show that a broad range of genes repressed during senescence is connected to the DREAM complex and might be critical for cell cycle exit or mitotic decline.…”

The Omnipresence of DYRK1A in Human Diseases

“…However, numerous biological targets have been studied in this context, including DYRK1A. Studies show that DYRK1A small molecule inhibitors induce human β-cell proliferation both in vitro and in vivo [ 54 , 78 , 114 , 115 , 116 , 117 , 118 ]. Several studies have demonstrated that DYRK1A overexpression attenuated β-cell proliferation through NFAT dysregulation, a transcription factor that transactivates cell cycle-activating genes and represses cell cycle inhibitor genes including other CMGC, cyclins and p57 ( Table 1 ) [ 30 , 68 , 114 , 115 ].…”

Promoting pancreatic β cell proliferation: A powerful key for realizing regenerative therapy for diabetes

“…Wang et al . 2 reported that they elucidated the regulation mechanism of pancreatic β cell proliferation, particularly via dual‐specificity tyrosine‐regulated kinase‐1a (DYRK1A) inhibition. The proliferation of pancreatic β cells has been thought to be mainly regulated by calcium ions.…”

“…The DREAM complex consists of a MuvB core (retinoblastoma binding protein 4 (RBBP4) and LIN9, LIN37, LIN52, and LIN54) and additional components 4 , converting its function to either repressive or proliferative depending on the additional components. When the MuvB complex binds to its repressive partners, p130, p107, and E2F4 or E2F5, the DREAM complex is referred to as DREAM repressive form 2 . The key to forming the repressive version of the DREAM complex is the phosphorylation of LIN52 by the kinase DYRK1A.…”

“…Wang et al . 2 hypothesized that the DREAM complex is a candidate to regulate cell proliferation in human pancreatic β cells. They asked whether these components were expressed in normal human β cells.…”