BAF (SWI/SNF) chromatin remodelers engage binding partners to generate site-specific DNA accessibility. However, the basis for interaction between BAF and divergent binding partners has remained unclear. Here, we tested the hypothesis that scaffold proteins augment BAF's binding repertoire by examining β-catenin (CTNNB1) and steroidogenic factor 1 (SF-1, NR5A1), a transcription factor central to steroid production in human cells. BAF inhibition rapidly opposed SF-1/β-catenin enhancer occupancy, impairing SF-1 target activation and SF-1/β-catenin autoregulation. These effects arise due to β-catenin's role as a molecular adapter between SF-1 and an intrinsically disordered region (IDR) of the canonical BAF (cBAF) subunit ARID1A. In contrast to exclusively IDR-driven mechanisms, adapter function is mediated by direct association of ARID1A with β-catenin's folded Armadillo repeats. β-catenin similarly linked cBAF to YAP1, SOX2, FOXO3, and CBP/p300, reflecting a general IDR-mediated mechanism for modular coordination between factors. Molecular visualization highlights β-catenin's adapter role for interaction of cBAF with binding partners.

• Klíčová slova
• IDRs, adrenocortical carcinoma, chromatin remodeling, co-activators, scaffold proteins, steroid hormones, transcription factors, transcription regulators, unstructured protein,
• MeSH
• adaptorové proteiny signální transdukční metabolismus   genetika   MeSH
• beta-katenin * metabolismus   genetika   chemie   MeSH
• DNA vazebné proteiny * metabolismus   genetika   chemie   MeSH
• fosfoproteiny metabolismus   genetika   MeSH
• HEK293 buňky MeSH
• jaderné proteiny * metabolismus   genetika   MeSH
• lidé MeSH
• protein FOXO3 metabolismus   genetika   MeSH
• signální proteiny YAP MeSH
• signální transdukce MeSH
• steroidogenní faktor 1 * metabolismus   genetika   MeSH
• transkripční faktory p300-CBP metabolismus   genetika   MeSH
• transkripční faktory * metabolismus   genetika   chemie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vnitřně neuspořádané proteiny * metabolismus   genetika   MeSH
• zesilovače transkripce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• ARID1A protein, human MeSH Prohlížeč
• beta-katenin * MeSH
• CTNNB1 protein, human MeSH Prohlížeč
• DNA vazebné proteiny * MeSH
• fosfoproteiny MeSH
• jaderné proteiny * MeSH
• NR5A1 protein, human MeSH Prohlížeč
• protein FOXO3 MeSH
• signální proteiny YAP MeSH
• steroidogenní faktor 1 * MeSH
• transkripční faktory p300-CBP MeSH
• transkripční faktory * MeSH
• vnitřně neuspořádané proteiny * MeSH
• YAP1 protein, human MeSH Prohlížeč

Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. We furthermore developed a new approach to analyze the oscillating patterns of genome-wide DNA accessibility across the cell cycle, which revealed that SWI/SNF-dependent CRC binding sites are enriched at enhancers with peak accessibility during G1 phase, where they activate genes involved in cell-cycle progression. SWI/SNF inhibition strongly impairs G1-S transition and potentiates the ability of retinoids used clinically to induce cell-cycle exit. Similar cell-cycle effects in diverse SWI/SNF-addicted settings highlight G1-S transition as a common cause of SWI/SNF dependency. Our results illustrate that deeper knowledge of the temporal patterns of enhancer-related dependencies may aid the rational targeting of addicted cancers.

Cancer cells driven by runaway transcription factor networks frequently depend on the cellular machinery that promotes DNA accessibility. For this reason, recently developed small molecules that impair SWI/SNF (or BAF) chromatin remodeling activity have been under active evaluation as anti-cancer agents. However, exactly when SWI/SNF activity is essential in dependent cancers has remained unknown. By combining live-cell imaging and genome-wide profiling in neuroblastoma cells, Cermakova et al. discover that SWI/SNF activity is needed for survival only during G1 phase of the cell cycle. The authors reveal that in several cancer settings, dependency on SWI/SNF arises from the need to reactivate factors involved in G1-S transition. Because of this role, authors find that SWI/SNF inhibition potentiates cell-cycle exit by retinoic acid.

• MeSH
• buněčný cyklus MeSH
• chromatin genetika   MeSH
• DNA MeSH
• G1 fáze * MeSH
• lidé MeSH
• nádory * MeSH
• regulační oblasti nukleových kyselin MeSH
• restrukturace chromatinu MeSH
• transkripční faktory * metabolismus   MeSH
• zesilovače transkripce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chromatin MeSH
• DNA MeSH
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transkripční faktory * MeSH