BRD4 Signaling Maintains the Differentiated State of β Cells
In diabetes, pancreatic β cells degenerate from their mature differentiated state to a dedifferentiated state. BRD4 plays a pivotal role during embryogenesis and cancer development, but its function in modulating β-cell differentiation remains unknown. In this study, multiple models including calorie restriction db/db mouse, long-term and acute conditional knockout mouse, and human islet organoids are adopted to assess BRD4 function in β cells. Two hundred twenty-two young patients with diabetes are also recruited for whole exome sequencing (WES) to screen for BRD4 mutations. This study shows that BRD4 expression is significantly reduced in human diabetic β cells while significantly increased after calorie restriction in the diabetic mouse. β cell differentiation is impaired after long-term and acute Brd4 knockout. BRD4 knockdown in human islet organoids results in the loss of differentiation and reduction of insulin synthesis. It is found that p.R749C can significantly affect BRD4 signaling and might play roles in diabetes development in patients. This study also shows that ATF5 is a direct target of the BRD4 pathway in β cells. Targeting BRD4-mediated regulatory networks may hold promise for developing novel therapeutic strategies to maintain the differentiated state of β cells.
Authors
- Mengmeng Yang (ORCID: https://orcid.org/0000-0001-9060-5940)
- Tixiao Wang (ORCID: https://orcid.org/0000-0002-7430-8484)
- Ying Zou (ORCID: https://orcid.org/0009-0002-1327-8418)
- Xinguo Hou (ORCID: https://orcid.org/0000-0003-2045-1290)
- Lei Zhao (ORCID: https://orcid.org/0000-0003-1360-5503)
- Qincheng Qiao (ORCID: https://orcid.org/0009-0009-7900-2984)
- Yuanyuan Du (ORCID: https://orcid.org/0000-0002-8293-328X)
- Suo Li (ORCID: https://orcid.org/0000-0002-9742-367X)
- Jingru Qu (ORCID: https://orcid.org/0000-0002-2786-4058)
- Huihui Tian
- Li Chen (ORCID: https://orcid.org/0000-0001-6007-0359)
- Yujing Sun (ORCID: https://orcid.org/0000-0002-5211-2974)
- Manna Zhang (ORCID: https://orcid.org/0000-0002-8445-1954)
- Hongkai Zhao
- Jie Chen (ORCID: https://orcid.org/0000-0002-7773-3160)
- Chenglong Yu (ORCID: https://orcid.org/0000-0003-4420-004X)
- Guang Liu (ORCID: https://orcid.org/0000-0003-0468-1061)
- Fuqiang Liu (ORCID: https://orcid.org/0000-0002-9950-3673)
- Tao Huang (ORCID: https://orcid.org/0009-0007-8196-2090)
- Jidong Liu (ORCID: https://orcid.org/0000-0002-1279-0279)
- Jia Song (ORCID: https://orcid.org/0000-0003-1706-162X)
- Hualin Liu (ORCID: https://orcid.org/0000-0001-9110-6297)
- Ruxing Zhao (ORCID: https://orcid.org/0000-0002-8893-1007)
Institutions
- Tongji University (CN)
- Shandong University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Ninth People's Hospital (CN)
- Hangzhou Academy of Agricultural Sciences (CN)
- Shanghai Tenth People's Hospital (CN)
- Shandong Women’s University (CN)
- Qilu Hospital of Shandong University (CN)
- Shandong First Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-06-20
- DOI
- https://doi.org/10.1002/advs.202505659
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- Taishan Scholar Foundation of Shandong Province
- National Science and Technology Major Project
- National Key Research and Development Program of China