Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells
Peng Wang1,2, Esra Karakose1,2, Carmen Argmann3
1Diabetes Obesity Metabolism Institute.
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.
Insights
Small molecule inhibitors of DYRK1A kinase promote human beta cell regeneration by disrupting the quiescent DREAM complex and activating the MMB complex, offering a new avenue for diabetes treatment.
Area of Science:
- Cell biology
- Endocrinology
- Molecular medicine
Background:
- Pancreatic beta cell regeneration is crucial for managing type 1 and type 2 diabetes.
- DYRK1A kinase inhibitors have shown promise in inducing beta cell proliferation, but their mechanism remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which DYRK1A inhibitors induce human beta cell proliferation.
- To identify key molecular regulators controlling beta cell quiescence and proliferation.
Main Methods:
- Comparative transcriptomic analysis of human insulinoma and normal beta cells.
- Investigation of protein complex assembly and function in response to DYRK1A activity.
- Assays to determine the effect of DYRK1A inhibitors on beta cell replication.
Main Results:
- The DREAM complex, a repressive protein module, maintains beta cell quiescence and is regulated by DYRK1A kinase activity.
- Inhibition of DYRK1A disrupts the DREAM complex.
- Disruption of the DREAM complex leads to the formation of the pro-proliferative MMB complex, inducing beta cell replication.
Conclusions:
- DYRK1A kinase activity stabilizes the repressive DREAM complex in human beta cells.
- Small molecule DYRK1A inhibitors promote beta cell proliferation by converting the DREAM complex to the MMB complex.
- Targeting the DREAM/MMB complex offers a potential therapeutic strategy for diabetes treatment.
