BRD2 phase separation activates super-enhancer-driven ATG7 transcription to promote ferritinophagy in depression

Depression is a psychiatric disorder which affects many aspects of the social life of patients; however, the molecular biological mechanisms underlying its development are not fully understood. Our research reveals that depression onset is associated with BRD2 LLPS-mediated activation of ATG7 super-enhancers (SEs), and we studied BRD2 liquid-liquid phase separation (LLPS) and super-enhancers in depression using chronic mild stress (CMS)-induced rat models and corticosterone-stimulated PC12 cell models. SEs enrichment, core transcription factor ARID5A and target gene ATG7 were found in the prefrontal cortex of depressed rats by ChIP-seq; through in vitro construction of phase separation droplets, fluorescent bleach recovery experiments (FRAP), and verification of the dual luciferase reporter gene, we found that BRD2 mediates transcription through LLPS, driving ATG7 transcriptional activation; while the BET inhibitor JQ1 reverses abnormal ATG7 activation and alleviates depressive behaviors and saving ferritinophagy in animal models of CMS.Our work is the first to elucidate the "phase separation-SEs-ferritinophagy" axis in depression pathogenesis, offering novel therapeutic strategies targeting epigenetic and phase separation mechanisms. It provides new ideas for the pathogenesis and treatment of depression.