PT  - JOURNAL ARTICLE
AU  - Lizhen Chen
AU  - Zhao Zhang
AU  - Qinyu Han
AU  - Leticia Rodrigues
AU  - Emily Zboril
AU  - Rashmi Adhikari
AU  - Xin Li
AU  - Su-Hyuk Ko
AU  - Pengya Xue
AU  - Emilie Smith
AU  - Kexin Xu
AU  - Qianben Wang
AU  - Tim Hui-Ming Huang
AU  - Shasha Chong
AU  - Zhijie Liu
TI  - Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions
AID  - 10.1101/2022.10.28.514297
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.28.514297
4099  - http://biorxiv.org/content/early/2022/10/30/2022.10.28.514297.short
4100  - http://biorxiv.org/content/early/2022/10/30/2022.10.28.514297.full
AB  - Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that Androgen Receptor (AR), a steroid hormone-regulated transcription factor, forms condensates through multivalent interactions in response to androgen signaling to orchestrate enhancer assembly. We demonstrate that the intrinsically disordered N-terminal domain (NTD) of AR drives 1,6-Hexanediol-sensitive condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by intrinsically disordered regions (IDRs) from selective proteins for AR condensation capacity and transactivation function. Surprisingly, strengthened AR condensation capacity caused by extending the polyQ tract within AR NTD also leads to impaired transcriptional activity without affecting AR binding on enhancers. Furthermore, either NTD deletion or polyQ extension reduces heterotypic multivalent interactions between AR and other enhancer components. These results suggest the importance of an optimal level of AR condensation in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate enhancer assembly in response to signals. Our study supports the notion that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies, thereby providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR multivalent interactions.Competing Interest StatementThe authors have declared no competing interest.