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

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.

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Publication Details

Journal
Nature Structural & Molecular Biology
Published
2024-09-20
DOI
https://doi.org/10.1038/s41594-024-01391-7
Citations
9
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
2.10
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article

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

Chaoyu Fu, Ying Zhang, Marek Mutwil, Yvonne Tay et al.
9 citations
Nature Structural & Molecular Biology
Genomics and Chromatin Dynamics
2.10
article

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

Chaoyu Fu, Ying Zhang, Marek Mutwil, Yvonne Tay, Jia Jia Chan, Akiko Nambu, Yi Xiang See, Kaijing Chen, Seng Chuan Tang, Motomi Osato, Daniel G. Tenen, Manikandan Lakshmanan, Greg Tucker‐Kellogg, Wee Joo Chng, Benjamin Lebeau, Melissa J. Fullwood, Yichao Cai, Vinay Tergaonkar, Zixun Ling, Anandhkumar Raju
article en
9 citations

Abstract

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.

Nature Structural & Molecular BiologyVol. 32(1)
Agency for Science, Technology and Research (SG), National University of Singapore (SG), Nanyang Technological University (SG), National University Cancer Institute, Singapore (SG), National Cancer Centre Singapore (SG), National University Health System (SG), Harvard Stem Cell Institute (US), Genome Institute of Singapore (SG)
Good health and well-being
Openalex Percentile: Top 12%
Genomics and Chromatin Dynamics
2.10
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