Work

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

Year: 2025

Type: article

Abstract: Background Depression is a psychiatric disorder which affects many aspects of social life of patients; however, the molecular biological mechanisms underlying its development are not fully understood. Atypical phase separation is a mechanism contributing to the occurrence of neurological disorders. The interaction between autophagy and iron metabolism have been implicated in the pathogenesis of neurological diseases. Methods To explore the pathogenesis of depression, we analyzed super-enhancers (SEs) in the prefrontal cortex of depression model rats using chromatin immunoprecipitation sequencing (ChIP-seq). The role of the upstream protein Bromodomain Containing 2 (BRD2) in super-enhancers (SEs) was investigated by synthesizing liquid-liquid phase separation proteins in vitro which were examined through Fluorescence recovery after photobleaching (FRAP) analysis. Moreover, the markers of ferritinophagy in cortisol-stimulated primary cortical neuron cells and PC12 cell models were explored to the occurrence of ferritinophagy in depression models. Results Rats exposed to chronic mild stress (CMS) exhibited decreased activation of autophagy-related 7 (ATG7) mediated by SEs. In rats subjected to CMS and in cellular models of depression, ferritinophagy was detected. Arid5a stimulated ATG7 activation via SEs and was influenced by the BET family and liquid-liquid phase separation. Ferritinophagy dysfunction in cellular models of depression was dependent on ATG7. BRD2 exhibited aberrant phase separation in CMS rats. The BET inhibitor JQ1 alleviated depressive behavior in rats subjected to CMS. Conclusions The ATG7 genes are activated by SEs in cellular and animal models of depression. The increased transcriptional activity of ATG7 can increase the risk of ferritinophagy. Moreover, the phase separation of BRD2 promotes ATG7 expression via SEs.

Source: Scientific Reports

DOI: 10.1038/s41598-025-21631-0