Myt Transcription Factors Prevent Stress-Response Gene Overactivation to Enable Postnatal Pancreatic β Cell Proliferation, Function, and Survival
| Autor: | Appakalai N. Balamurugan, Yan Li, Chen Huang, Guoqiang Gu, Chen Weng, Irina Kaverina, Yanwen Xu, Xiaodun Yang, Marcela Brissova, Emily M. Walker, Roland Stein, Gillian E. Erickson, Ruiying Hu, Christopher V.E. Wright, Anastasia Coldren |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Activating transcription factor Biology Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Stress Physiological Insulin-Secreting Cells Heat shock protein Cellular stress response Insulin Secretion Diabetes Mellitus Animals Humans Enhancer Molecular Biology Transcription factor Heat-Shock Proteins Cell Proliferation 030304 developmental biology Mice Knockout 0303 health sciences Gene knockdown ATF4 Cell Biology Activating Transcription Factor 4 Cell biology DNA-Binding Proteins Female 030217 neurology & neurosurgery Transcription Factors Developmental Biology |
| Zdroj: | Dev Cell |
| ISSN: | 1534-5807 |
| Popis: | Although cellular stress response is important for maintaining function and survival, overactivation of late-stage stress effectors cause dysfunction and death. We show that the myelin transcription factors (TFs) Myt1 (Nzf2), Myt2 (Myt1l, Nztf1, and Png-1), and Myt3 (St18 and Nzf3) prevent such overactivation in islet β cells. Thus, we found that co-inactivating the Myt TFs in mouse pancreatic progenitors compromised postnatal β cell function, proliferation, and survival, preceded by upregulation of late-stage stress-response genes activating transcription factors (e.g., Atf4) and heat-shock proteins (Hsps). Myt1 binds putative enhancers of Atf4 and Hsps, whose overexpression largely recapitulated the Myt-mutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in mouse and human β cells during metabolic stress-induced compensation but downregulated in dysfunctional type 2 diabetic (T2D) human β cells. Lastly, MYT knockdown caused stress-gene overactivation and death in human EndoC-βH1 cells. These findings suggest that Myt TFs are essential restrictors of stress-response overactivity. |
| Databáze: | OpenAIRE |
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