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

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.