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Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

ABSTRACT: Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

PROVIDER: PRJNA889014 | ENA |

REPOSITORIES: ENA

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Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

Project description:Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

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Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

Project description:Transcription factors (TFs) activate enhancers to drive cell-specific gene expression in response to signals, but our understanding of enhancer assembly in signaling events is incomplete. Here we show that Androgen Receptor (AR), a steroid hormone signaling-regulated transcription factor, forms phase-separated condensates in response to androgen to activate enhancers. We demonstrate that the intrinsically disordered NTD of AR drives 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 some IDRs from other proteins for AR condensation capacity and transactivation function. Extending the polyQ tract within AR NTD strengthens AR phase separation and also leads to impaired transcriptional activity. PolyQ expansion does not affect AR binding on enhancers, but instead impairs enhancer assembly. These results suggest that AR phase separation mediates enhancer assembly, and an optimal level of AR condensation is required for its proper function in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate transcription in response to signals. Our study supports that alteration of the fine-tuned protein condensation might underlie AR-related human pathologies, therefore providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR condensation.

2023-10-31 | GSE215160 | GEO

Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-31 | GSE215163 | GEO

Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping [RNA-seq]

Project description:Synthetic transcriptional activators based on CRISPR/Cas technology can be enhanced by intrinsically disordered regions (IDRs). However, the potential of all IDRs in this regard remains uncertain, and the mechanisms underlying their influence are a subject of debate. Here, we examined 12 well-known IDRs by fusing them to the dCas9-VP64 activator. Our findings reveal that seven IDRs could augment activation, albeit independently of their phase separation properties. Moreover, modular domains (MDs), which facilitate multivalent interactions but are ineffective in enhancing dCas9-VP64 activity on their own, showed substantial enhancement in transcriptional activation when combined with dCas9-VP64-IDR. By varying the number of gRNA binding sites and combining dCas9-VP64 with the IDRs and MDs of different multivalent capabilities, we uncovered that optimal, rather than maximal, cis-trans cooperativity enables the most robust activation. Finally, targeting promoter-enhancer pairs with our IDR-enhanced activation system yielded synergistic effects, potentially further amplifiable by induced functional chromatin looping.

2024-06-01 | GSE248523 | GEO

Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping [ChIA-PET]

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Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [ChIP-Seq]

Project description:Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [ChIP-Seq]

| PRJNA889015 | ENA

Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [GRO-Seq]

Project description:Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [GRO-Seq]

| PRJNA889017 | ENA

Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [GRO-Seq]

2023-10-31 | GSE215162 | GEO

Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [ChIP-Seq]

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Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping.

Project description:Specific multivalent molecules boost CRISPR-mediated transcriptional activation via optimal cis-trans interaction and functional chromatin looping.

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