journal article·2025-09Open access

BRD4 Signaling Maintains the Differentiated State of β Cells

Fuqiang Liu, Guang Liu, Jia Song, Yujing Sun, Mengmeng Yang, Hualin Liu, Hongkai Zhao, Jiamu Chen, Qincheng Qiao, Siyue Li, Chenglong Yu, Jingru Qu, Ying Zou, Tixiao Wang, Jidong Liu, Lei Zhao, Huihui Tian, Tao Huang, Manna Zhang, Li Chen, Ruxing Zhao, Yuanyuan Du, Xinguo Hou

Advanced Science· Volume 12· Issue 33

Abstract

Abstract 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.
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Research context

OpenAlex topics: Pancreatic function and diabetes · Protein Degradation and Inhibitors · Genetics and Neurodevelopmental Disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Endocrinology and Metabolism Qilu Hospital of Shandong University Jinan Shandong 250012 China

Shandong Provincial Key Laboratory of Spatiotemporal Regulation and Precision Intervention in Endocrine and Metabolic Diseases Shandong Provincial Engineering Research Center for Advanced Technologies in Prevention and Treatment of Chromic Metabolic Diseases Institute of Endocrine and Metabolic Diseases of Shandong University Jinan Shandong 250012 China

Department of Vascular Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200011 China

The First Clinical Medical College Cheeloo College of Medicine Shandong University Jinan 250012 China

Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310006 China

Research Center for Basic Medical Sciences Qilu Hospital of Shandong University Jinan China 250012

Jinan AXZE Medical Test Laboratory Jinan Shandong Province 250101 China

Institute of Women Children and Reproductive Health Shandong University Jinan Shandong 250012 China

Department of General Practice Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai China 200072

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Taishan Scholar Foundation of Shandong Province

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