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...
Saved in:
Main Authors: | , , , , , , , , , , , , , , , , , , , |
---|---|
Other Authors: | |
Format: | Article |
Language: | English |
Published: |
2024
|
Subjects: | |
Online Access: | https://hdl.handle.net/10356/180582 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Institution: | Nanyang Technological University |
Language: | English |
id |
sg-ntu-dr.10356-180582 |
---|---|
record_format |
dspace |
institution |
Nanyang Technological University |
building |
NTU Library |
continent |
Asia |
country |
Singapore Singapore |
content_provider |
NTU Library |
collection |
DR-NTU |
language |
English |
topic |
Medicine, Health and Life Sciences Chromatin structure Gene silencing |
spellingShingle |
Medicine, Health and Life Sciences Chromatin structure Gene silencing Zhang, Ying Chen, Kaijing Tang, Seng Chuan Cai, Yichao Nambu, Akiko See, Yi Xiang Fu, Chaoyu Raju, Anandhkumar Lebeau, Benjamin Ling, Zixun Chan, Jia Jia Tay, Yvonne Mutwil, Marek Lakshmanan, Manikandan Tucker-Kellogg, Greg Chng, Wee Joo Tenen, Daniel G Osato, Motomi Tergaonkar, Vinay Fullwood, Melissa Jane Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth |
description |
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. |
author2 |
School of Biological Sciences |
author_facet |
School of Biological Sciences Zhang, Ying Chen, Kaijing Tang, Seng Chuan Cai, Yichao Nambu, Akiko See, Yi Xiang Fu, Chaoyu Raju, Anandhkumar Lebeau, Benjamin Ling, Zixun Chan, Jia Jia Tay, Yvonne Mutwil, Marek Lakshmanan, Manikandan Tucker-Kellogg, Greg Chng, Wee Joo Tenen, Daniel G Osato, Motomi Tergaonkar, Vinay Fullwood, Melissa Jane |
format |
Article |
author |
Zhang, Ying Chen, Kaijing Tang, Seng Chuan Cai, Yichao Nambu, Akiko See, Yi Xiang Fu, Chaoyu Raju, Anandhkumar Lebeau, Benjamin Ling, Zixun Chan, Jia Jia Tay, Yvonne Mutwil, Marek Lakshmanan, Manikandan Tucker-Kellogg, Greg Chng, Wee Joo Tenen, Daniel G Osato, Motomi Tergaonkar, Vinay Fullwood, Melissa Jane |
author_sort |
Zhang, Ying |
title |
Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth |
title_short |
Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth |
title_full |
Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth |
title_fullStr |
Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth |
title_full_unstemmed |
Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth |
title_sort |
super-silencer perturbation by ezh2 and rest inhibition leads to large loss of chromatin interactions and reduction in cancer growth |
publishDate |
2024 |
url |
https://hdl.handle.net/10356/180582 |
_version_ |
1814777777446977536 |
spelling |
sg-ntu-dr.10356-1805822024-10-14T15:32:28Z Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth Zhang, Ying Chen, Kaijing Tang, Seng Chuan Cai, Yichao Nambu, Akiko See, Yi Xiang Fu, Chaoyu Raju, Anandhkumar Lebeau, Benjamin Ling, Zixun Chan, Jia Jia Tay, Yvonne Mutwil, Marek Lakshmanan, Manikandan Tucker-Kellogg, Greg Chng, Wee Joo Tenen, Daniel G Osato, Motomi Tergaonkar, Vinay Fullwood, Melissa Jane School of Biological Sciences Cancer Science Institute of Singapore Institute of Molecular and Cell Biology, A*STAR Medicine, Health and Life Sciences Chromatin structure Gene silencing 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. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Submitted/Accepted version This research was supported by a National Research Foundation Competitive Research Program grant awarded to V.T. as the lead principal investigator (PI) and M.J.F. as the co-PI (NRF-CRP17-2017-02). This research was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative. This research was supported by the Ministry of Education, Singapore under its Academic Research Fund Tier II grant (MOE-T2EP30120-0009) awarded to M.J.F. (PI) and the Ministry of Education, Singapore under its Academic Research Fund Tier 1 Thematic (RT5/22) awarded to M.J.F. (PI). This research was supported by the Central Research Fund from the Agency for Science, Technology and Research (A*STAR), National Research Foundation (award no. NRF-CRP26-2021-0001) and the National Medical Research Council (award no. OFIRG21jun-0101). This research was supported by the National Research Foundation Singapore under its Open Fund - Individual Research Grant (MOH-001387) and administered by the Singapore Ministry of Health’s National Medical Research Council awarded to M.J.F. (PI). 2024-10-14T02:45:27Z 2024-10-14T02:45:27Z 2024 Journal Article Zhang, Y., Chen, K., Tang, S. C., Cai, Y., Nambu, A., See, Y. X., Fu, C., Raju, A., Lebeau, B., Ling, Z., Chan, J. J., Tay, Y., Mutwil, M., Lakshmanan, M., Tucker-Kellogg, G., Chng, W. J., Tenen, D. G., Osato, M., Tergaonkar, V. & Fullwood, M. J. (2024). Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth. Nature Structural & Molecular Biology. https://dx.doi.org/10.1038/s41594-024-01391-7 1545-9993 https://hdl.handle.net/10356/180582 10.1038/s41594-024-01391-7 39304765 2-s2.0-85204604460 en NRF-CRP17-2017-02 MOE-T2EP30120-0009 RT5/22 NRF-CRP26-2021-0001 OFIRG21jun-0101 MOH-001387 Nature Structural & Molecular Biology © 2024 The Author(s). This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. application/pdf |