The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes
| Autor: | Laura Leonhardt, Tanya Vavouri, Chih-Hsiang Yang, Brad G. Hoffman, Tess Tsai Hsiu Lu, Ulrike Boenisch, Marius Ruf, Francis C. Lynn, Steffen Heyne, Laura Arrigoni, Thorina Boenke, Stuart H. Orkin, Huafeng Xie, Eduard Casas, Dominic Grün, Lennart Enders, Sunil Jayaramaiah Raja, Erez Dror, J. Andrew Pospisilik, Kevin Dalgaard, Sagar, Adelheid Lempradl, Madhan Selvaraj, Raffaele Teperino |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Epigenomics
0301 basic medicine Physiology Cell Subclass Transcriptome Mice 0302 clinical medicine Insulin-Secreting Cells Transcriptional regulation Cells Cultured Eed β cells de-differentiation type 2 diabetes diabetes Polycomb epigenetic chromatin cell identity complex diseases Eed Mice Knockout Genetics 0303 health sciences diabetes biology Polycomb Repressive Complex 2 Chromosome Mapping Cell Differentiation β cells Chromatin Cell biology medicine.anatomical_structure type 2 diabetes Single-Cell Analysis PRC2 epigenetic Myeloid-Lymphoid Leukemia Protein Genomics macromolecular substances Diet High-Fat Article 03 medical and health sciences Diabetes Mellitus medicine Animals Humans complex diseases Gene Silencing Epigenetics Gene Molecular Biology Loss function Cell Proliferation 030304 developmental biology de-differentiation Histone-Lysine N-Methyltransferase Cell Biology Epigenome Polycomb Mice Inbred C57BL 030104 developmental biology Diabetes Mellitus Type 2 Hyperglycemia biology.protein cell identity 030217 neurology & neurosurgery |
| Zdroj: | Cell Metabolism Cell Metab. 27, 1294-1308.e7 (2018) r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol instname |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2018.04.013 |
| Popis: | Summary To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track β cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. β cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring β cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of β cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes. Graphical Abstract Highlights • Deep epigenome mapping and single-cell transcriptomics of β cells in T2D • Human and mouse diabetes mimic PRC2 loss of function • Eed/PRC2 safeguards transcription integrity in terminally differentiated β cells • Eed/PRC2-sensitive dedifferentiation is pharmacologically targetable Lu et al. provide evidence of chromatin dysregulation in type 2 diabetes in mice and humans. Loss of Polycomb silencing in mouse pancreas triggers hyperglycemia-independent dedifferentiation of β cells and diabetes, suggesting a two-hit (chromatin and hyperglycemia) model for loss of β cell identity in diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|