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journal article·2026-05-07Open access

Dose‐Dependent Reprogramming of Chromatin Accessibility by SOX4 Drives the Transcriptional Response to Iron Overload

Feifei Li, Yaoqiu Wu, Guangyu Yang, Jingyi Lai, Xiaoyue Sun, Liyan Wang, Xiaoli Li, Jing Zhang, Qingxue Zhang, Hui Chen, Haiyan Lin, Bingxiang Xu, Junfeng Zhang, Hailong Wang, Anming Meng, Chunwei Cao

Advanced Science
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Abstract

ABSTRACT Iron overload induces cellular stress and is implicated in diverse pathological conditions. Nevertheless, the epigenetic mechanisms governing mammalian cellular responses to iron overload remain poorly characterized. Using multi‐omics profiling in human granulosa cells, we show that the transcriptional signature of iron‐stressed granulosa cells recapitulated that of granulosa cells from endometriosis patients. Mechanistically, iron excess triggered a time‐dependent, genome‐wide reduction in chromatin accessibility, which was associated with broad transcriptional suppression. Furthermore, fine‐scale chromatin looping underwent dynamic reorganization, concomitant with dysregulated expression of core iron metabolism genes. We identify SOX4 as a central, dosage‐sensitive regulator of this epigenetic reprogramming: its downregulation under iron stress drives chromatin compaction, while ectopic SOX4 expression largely restores accessibility. Moreover, SOX4 is directly regulated by TFEB through binding to the CLEAR motif in its promoter and, in turn, exerts its function by recruiting the SWI/SNF chromatin remodeling complex. Notably, SOX4 also mediated chromatin compaction under high‐androgen stimulation, suggesting its universal role as a stress‐responsive epigenetic regulator in granulosa cells. These results elucidate a TFEB‐SOX4‐SWI/SNF regulatory axis that orchestrates iron‐responsive chromatin plasticity, and more broadly, uncover SOX4 as a key mediator of chromatin adaptation to pathophysiological stressors, including iron overload and hyperandrogenism.
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Research context

OpenAlex topics: Chromatin Remodeling and Cancer · Genomics and Chromatin Dynamics · Reproductive System and Pregnancy

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

Affiliations

Division of Cell Developmental and Integrative Biology School of Medicine South China University of Technology Guangzhou China

Shenzhen Maternity and Child Healthcare Hospital Women and Children's Medical Center Southern Medical University Shenzhen Guangdong China

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou China

Guangzhou National Laboratory Guangzhou China

Laboratory of Developmental Biology Department of Cell Biology and Genetics School of Basic Medical Sciences Chongqing Medical University Chongqing China

Department of Obstetrics and Gynecology Sun Yat‐sen Memorial Hospital of Sun Yat‐Sen University Guangzhou China

Key Laboratory of Hebei Province for Molecular Biophysics Institute of Biophysics School of Health Science & Biomedical Engineering Hebei University of Technology Tianjin China

Laboratory of Molecular Developmental Biology State Key Laboratory of Membrane Biology Tsinghua‐Peking Center for Life Sciences School of Life Sciences Tsinghua University Beijing China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province · Fundamental Research Funds for the Central Universities

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