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ResearchIn-Press PreviewEndocrinology Open Access | 10.1172/JCI157086

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

Peng Wang,1 Esra Karakose,2 Carmen Argmann,3 Huan Wang,4 Metodi Balev,5 Rachel I. Brody,6 Hembly G. Rivas,7 Xinyue Liu,7 Olivia Wood,1 Hongtao Liu,1 Lauryn Choleva,8 Dan Hasson,9 Emily Bernstein,10 Joao A. Paulo,7 Donald K. Scott,11 Luca Lambertini,12 James A. DeCaprio,13 and Andrew F. Stewart.14

1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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1Diabetes Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

3Department of Genomics and Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America

4Bioinformatics Scientist, Sema4, Stamford, United States of America

5Diabetes Obesith Metabolism Institue, Icahn School of Medicine at Mount Sinai, New York, United States of America

6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States of America

7Department of Cell Biology, Harvard Medical School, Boston, United States of America

8Pediatrics, Icahn School of Medicine, New York, United States of America

9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Oncological Sciences, Mount Sinai School of Medicine, New York, United States of America

11Obesity, Diabetes and Metabolism Institute, Icahn school of medicine at Mt. Sinai, New York, United States of America

12Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

13Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’, Boston, United States of America

14Director, Diabetes, Obesity and Metabolism Institute, Mount Sinai School of Medicine, New York, United States of America

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Published June 14, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI157086.
Copyright © 2022, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 14, 2022 - Version history
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Abstract

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

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graphical abstract
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  • Version 1 (June 14, 2022): In-Press Preview
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