Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth.

Autor: Zhang Y; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Chen K; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Tang SC; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Cai Y; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Nambu A; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., See YX; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Fu C; Mechanobiology Institute, National University of Singapore, Singapore, Singapore., Raju A; Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Lebeau B; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Ling Z; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Chan JJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Tay Y; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore., Mutwil M; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Lakshmanan M; Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Tucker-Kellogg G; Department of Biological Sciences, National University of Singapore, Singapore, Singapore.; Computational Biology Programme, Faculty of Science, National University of Singapore, Singapore, Singapore., Chng WJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; NUS Centre for Cancer Research (N2CR), Centre for Translational Medicine, Singapore, Singapore.; Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Health System (NUHS), Singapore, Singapore., Tenen DG; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.; Harvard Stem Cells Institute, Harvard Medical School, Boston, MA, USA., Osato M; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Tergaonkar V; Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore., Fullwood MJ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. mfullwood@ntu.edu.sg.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. mfullwood@ntu.edu.sg.; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. mfullwood@ntu.edu.sg.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Sep 20. Date of Electronic Publication: 2024 Sep 20.
DOI: 10.1038/s41594-024-01391-7
Abstrakt: Human silencers have been shown to regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form 'super-silencers' and whether they are linked to cancer progression. Here, we show two silencer components of the FGF18 gene can cooperate through compensatory chromatin interactions to form a super-silencer. Double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes in cell identity. To perturb the super-silencers, we applied combinational treatment of an enhancer of zeste homolog 2 inhibitor GSK343, and a repressor element 1-silencing transcription factor inhibitor, X5050 ('GR'). Interestingly, GR led to severe loss of topologically associated domains and loops, which were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GR synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects in vivo. Overall, our data demonstrated a super-silencer example and showed that GR can disrupt super-silencers, potentially leading to cancer ablation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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