Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells
Peng Wang, … , James A. DeCaprio, Andrew F. Stewart
Peng Wang, … , James A. DeCaprio, Andrew F. Stewart
Published June 14, 2022
Citation Information: J Clin Invest. 2022;132(15):e157086. https://doi.org/10.1172/JCI157086.
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Research Article Endocrinology

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.

Authors

Peng Wang, Esra Karakose, Carmen Argmann, Huan Wang, Metodi Balev, Rachel I. Brody, Hembly G. Rivas, Xinyue Liu, Olivia Wood, Hongtao Liu, Lauryn Choleva, Dan Hasson, Emily Bernstein, Joao A. Paulo, Donald K. Scott, Luca Lambertini, James A. DeCaprio, Andrew F. Stewart

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Figure 2

Conventional cell cycle control, DREAM complex anatomy, and human insulinoma bioinformatics.

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Conventional cell cycle control, DREAM complex anatomy, and human insuli...
(A) Conventional model of cell cycle molecules that regulate transition from G0 into G1 and S phases of the mammalian cell cycle (see refs. 32, 33 for reviews). (B) The 2 configurations of the mammalian DREAM and MMB complexes (see the Introduction and refs. 38–46 for details). (C) The predicted targets in the Bisque4 module membership group of these transcriptional regulators are shown as a network. An enlarged version is shown in Supplemental Figure 3. Nodes are colored according to the predicted transcriptional regulator they are in the network (yellow = FOXM1; cyan = MYBL2; green = TFDP1; orange = E2F4). Genes (nodes) that have edges/connections coming from multiple transcription factors (TFs) are colored gray. See main text for details. (D) The iRegulon tool was used to explore the predicted upstream transcriptional regulators of the Bisque4 module membership group of 253 genes derived from the WGCNA of a cohort of human insulinomas (Supplemental Figure 2) (46). The top TFs predicted by iRegulon, namely, E2F4, TFDP1, MYBL2, and FOXM1, are all canonical DREAM complex members (see Supplemental Table 3 for full results). For the normalized enrichment score, anything above 3.0 was considered significant. “# targets” indicate the number of genes predicted as targets of that TF that were found in the gene set of interest. Databases associated with binding motifs (M) or Encode ChIP-seq tracks (T) were surveyed within iRegulon.