Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF

0580756 - ÚOCHB 2025 RIV US eng J - Journal Article
Cermakova, K. - Tao, L. - Dejmek, Milan - Šála, Michal - Montierth, M. D. - Chan, Y. S. - Patel, I. - Chambers, C. - Loeza Cabrera, M. - Hoffman, D. - Parchem, R. J. - Wang, W. - Nencka, Radim - Barbieri, E. - Hodges, H. C.
Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF.
Nucleic Acids Research. Roč. 52, č. 1 (2024), s. 4-21. ISSN 0305-1048. E-ISSN 1362-4962
Institutional support: RVO:61388963
Keywords : neuroblastoma * differentiation * transcription
OECD category: Organic chemistry
Impact factor: 14.9, year: 2022
Method of publishing: Open access
https://doi.org/10.1093/nar/gkad1081

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.
Permanent Link: https://hdl.handle.net/11104/0349518


Research data: ZENODO, NCBI GEO