PRMT1 Is Required for the Maintenance of Mature β-Cell Identity
- 1 March 2020
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (3), 355-368
- https://doi.org/10.2337/db19-0685
Abstract
Loss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet–induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility.Keywords
Funding Information
- National Research Foundation (NRF-2013M3A9D5072550, NRF-2017M3C9A5028693, NRF-2014M3A9D5A01073546, NRF-2018R1A2A3074646, NRF-2015M3A9B3028218)
- Korea Research Institute of Bioscience and Biotechnology Research Initiative
- Korea Advanced Institute of Science and Technology Institute for the BioCentury (N10180027)
This publication has 54 references indexed in Scilit:
- PAX6 maintains β cell identity by repressing genes of alternative islet cell typesJCI Insight, 2016
- LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cellsJCI Insight, 2016
- Pancreatic β cell identity requires continual repression of non–β cell programsJCI Insight, 2016
- Stress‐induced adaptive islet cell identity changesDiabetes, Obesity and Metabolism, 2016
- MafA is critical for maintenance of the mature beta cell phenotype in miceDiabetologia, 2014
- β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and TreatmentDiabetes Care, 2014
- Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell FailureCell, 2012
- Pancreatic β Cells Require NeuroD to Achieve and Maintain Functional MaturityCell Metabolism, 2010
- Islet cell failure in type 2 diabetesJCI Insight, 2006
- Mechanisms of β-Cell Death in Type 2 DiabetesDiabetes, 2005