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The Polycomb-Dependent Epigenome Controls β Cell Cysfunction, Dedifferentiation, and Diabetes

MPG-Autoren

Lu,  Tess Tsai-Hsiu
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Heyne,  Steffen
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Dror,  Erez
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Leonhardt,  Laura
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Boenke,  Thorina
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Yang,  Chih-Hsiang
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sagar,  Sagar
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Arrigoni,  Laura
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Dalgaard,  Kevin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Teperino,  Raffaele
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Enders,  Lennart
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Selvaraj,  Madhan
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Ruf,  Marius
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Raja,  Sunil J.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Boenisch,  Ulrike
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Grün,  Dominic
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lempradl,  Adelheid M.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Pospisilik,  J. Andrew
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Zitation

Lu, T.-T.-H., Heyne, S., Dror, E., Casas, E., Leonhardt, L., Boenke, T., et al. (2018). The Polycomb-Dependent Epigenome Controls β Cell Cysfunction, Dedifferentiation, and Diabetes. Cell Metabolism, 15, 1294-1308. doi:doi.org/10.1016/j.cmet.2018.04.013.


Zitierlink: http://hdl.handle.net/21.11116/0000-0001-F751-D
Zusammenfassung
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.