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.
| Original language | English |
|---|---|
| Pages (from-to) | 355-368 |
| Number of pages | 14 |
| Journal | Diabetes |
| Volume | 69 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2020 Mar 1 |
Bibliographical note
Funding Information:Acknowledgments. The authors thank Hee-Saeng Jung, Jueun Kim, and Hanna Jung (Korea Advanced Institute of Science and Technology) for technical support, Dr. Dahee Choi (Korea University) and Hyun Jung Hong (Chungnam National University) for technical advice and support, Drs. Yong-Ho Ahn and Joo-Man Park (Yonsei University) for help with electron microscopic analysis, Jeong-Hwan Kim (Korea Research Institute of Bioscience and Biotechnology) for technical assistance with next-generation sequencing library preparation, Drs. Kyong Soo Park (Seoul National University), Kun-Ho Yoon (Catholic University of Korea), Soo Heon Kwak (Seoul National University), and Kyoung-Jae Won (University of Copenhagen) for helpful discussions, and Drs. Mark O. Huising (University of California, Davis) and Paul E. Sawchenko (Salk Institute) for the gift of the UCN3 antibody. Funding. This work was supported by grants from the National Research Foundation funded by the Ministry of Science, ICT and Future Planning, Republic of Korea (grants NRF-2013M3A9D5072550 to J.K.S., NRF-2017M3C9A5028693 to M.K., and NRF-2014M3A9D5A01073546, NRF-2018R1A2A3074646, and NRF-2015M3A9B3028218 to Hai. Kim), the Korea Research Institute of Bioscience and Biotechnology Research Initiative (to M.K.), and the Korea Advanced Institute of Science and Technology Institute for the BioCentury (grant N10180027 to Hai. Kim). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Hyu. Kim, B.-H.Y., C.-M.O., Jo. Lee, M.K., and Hai. Kim generated the hypothesis, designed the experiments, and analyzed the results. Hyu. Kim, C.-M.O., Jo. Lee, K.L., H.S., M.-Y.K., Hye. Kim, Y.K.K., and J.K.S. performed the animal experiments. Hyu. Kim, C.-M.O., E.K., E.-H.S., H.H., H.-J.K., Ju. Lee, J.M.S., S.-H.K., S.K., and M.S. performed the cell and in vitro experiments. Hyu. Kim, B.-H.Y., C.-M.O., K.Y., Y.S.J., M.K., and Hai. Kim analyzed the next-generation sequencing data. Hyu. Kim, B.-H.Y., C.-M.O., Jo. Lee, M.K., and Hai. Kim wrote the manuscript. M.K. and Hai. Kim supervised the research. M.K. and Hai. Kim are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the Drivers of Type 2 Diabetes: From Genes to Environment (S1) conference of the Keystone Symposia, Seoul, Republic of Korea, 7–11 October 2018, and at the Third Joint EASD Islet Study Group and Beta Cell Workshop, Oxford, U.K., 1–3 April 2019.
Funding Information:
This work was supported by grants from the National Research Foundation funded by the Ministry of Science, ICT and Future Planning, Republic of Korea (grants NRF-2013M3A9D5072550 to J.K.S., NRF-2017M3C9A5028693 to M.K., and NRF-2014M3A9D5A01073546, NRF-2018R1A2A3074646, and NRF-2015M3A9B3028218 to Hai. Kim), the Korea Research Institute of Bioscience and Biotechnology Research Initiative (to M.K.), and the Korea Advanced Institute of Science and Technology Institute for the BioCentury (grant N10180027 to Hai. Kim).
Publisher Copyright:
© 2019 by the American Diabetes Association.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
