BAF60a-dependent chromatin remodeling preserves β cell function and contributes to the therapeutic benefits of GLP-1R agonists

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Investigation
Published
2025-10-02
DOI
https://doi.org/10.1172/jci177980
Primary Topic
Pancreatic function and diabetes
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

BAF60a-dependent chromatin remodeling preserves β cell function and contributes to the therapeutic benefits of GLP-1R agonists

Ping Luo, Hongxing Fu, Zhuo‐Xian Meng, Xinyuan Qiu et al.
Journal of Clinical Investigation
Pancreatic function and diabetes
article

BAF60a-dependent chromatin remodeling preserves β cell function and contributes to the therapeutic benefits of GLP-1R agonists

Ping Luo, Hongxing Fu, Zhuo‐Xian Meng, Xinyuan Qiu, Dandan Yan, Lingyun Zhu, Guoji Guo, Hai‐long Piao, Ruo‐Ran Wang, Qingqian Wu, Cheng Hu, Wen Wang, Haide Chen, Qintao Wang, Min Zheng, Wei Chen, Wenjing Zhang, Rong Zhang, Bin Liang, Jing Yan, Jin Li, Ziyin Zhang, Sheng Yan, Wei Ding, Chengbin Li, Xiuyu Ji, Yingqing Yang, Shuaishuai Zhu, Xiaowen Pan, Mengjie Shi
article en

Abstract

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion.

Journal of Clinical InvestigationVol. 135(23)
National University of Defense Technology (CN), Dalian Institute of Chemical Physics (CN), Shanghai Jiao Tong University (CN), Yunnan University (CN), Chinese Academy of Sciences (CN), Sir Run Run Shaw Hospital (CN), Huzhou Normal University (CN), Institute for Stem Cell Biology and Regenerative Medicine (IN), Xian Central Hospital (CN), Zhejiang Hospital (CN), Lee's Pharmaceutical (China) (CN), Shanghai Sixth People's Hospital (CN), Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN), Second Affiliated Hospital of Zhejiang University (CN), Center for Life Sciences (CN), University of Chinese Academy of Sciences (CN), First Affiliated Hospital Zhejiang University (CN), Southern Medical University (CN), Zhejiang University (CN)
Openalex Percentile: Top 56%
Pancreatic function and diabetes
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.