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Published March 24, 2023 | Supplemental Material + Submitted
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Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

Abstract

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.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. Z.L. is a CPRIT Scholar in Cancer Research. This work was supported by funds from CPRIT RR160017 to Z.L., V Foundation V2016-017 to Z.L., V Foundation DVP2019-018 to Z.L., Voelcker Fund Young Investigator Award to Z.L., UT Rising STARs Award to Z.L., Susan G. Komen CCR Award CCR17483391 to Z.L., NCI U54 CA217297/PRJ001 to Z.L., the Mary Kay Foundation Cancer Research Grant to Z.L., Voelcker Fund Young Investigator Award to L.C., NIA R01AG070214 to L.C., and NIA R01AG071591 to L.C., Pew-Stewart Scholar Award to S.C., Searle Scholar Award to S.C., the Shurl and Kay Curci Foundation Research Grant to S.C., and Merkin Innovation Seed Grant for S.C.. Research reported in this publication was also supported by the NIGMS of the NIH under Award Number R01GM137009 to Z. Liu. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We would like to thank all the members of Liu and Chen labs for technical assistance and helpful discussion, especially for Dr. Mingjun Bi for his technical support on ATAC-seq and ChIP-seq and Dr. Jian Gao for his help with imaging and 1,6 HD treatment work. Author Contributions. Z.L., L.C., and S.C. conceived the work and designed the study. L.C., Z.L., Q.H., L.R., and E.Z. performed experiments and data analyses with assistance from R.A., X.L., S.K., P.X., and E.S.. Z.Z. performed the computational analyses for all next-generation sequencing assays. Z.L. supervised the research and oversaw the project. L.C. and Z.L. wrote the manuscript with input from all authors. K.X., Q.W., and T. H. provided comments and reviewed the manuscript. The authors have declared no competing interest.

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Additional details

Created:
October 9, 2023
Modified:
October 24, 2023