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

ABSTRACT: Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers need to be elucidated such as the working mode and whether they can form “super-silencers”. Here, through interrogating two putative silencer components of FGF18 gene, we found that two silencers can cooperate via compensated chromatin interactions to form the “super-silencer”. Furthermore, double knock-out of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To disturb the “super-silencers”, we applied the combinational treatment of GSK343 and X5050 (“GR”). We found that GR led to severe loss of TADs and loops, while any single treatment only had mild changes. Such changes of TADs and loops may due to the decreased CTCF proteins upon the GR treatment. Moreover, GSK343 and X5050 can work synergistically to upregulated the super-silencer controlled apoptotic genes, thus gave rise to antitumor effects including apoptosis, cell cycle arrest and tumor growth inhibition. Overall, our data demonstrated the first example of “super-silencer” and showed that combinational usage of GSK343 and X5050 maybe the potential drug to curing cancers through disruption of “super-silencers”.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193484 | GEO | 2024/05/08

REPOSITORIES: GEO

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

Project description:Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers need to be elucidated such as the working mode and whether they can form “super-silencers”. Here, through interrogating two putative silencer components of FGF18 gene, we found that two silencers can cooperate via compensated chromatin interactions to form the “super-silencer”. Furthermore, double knock-out of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To disturb the “super-silencers”, we applied the combinational treatment of GSK343 and X5050 (“GR”). We found that GR led to severe loss of TADs and loops, while any single treatment only had mild changes. Such changes of TADs and loops may due to the decreased CTCF proteins upon the GR treatment. Moreover, GSK343 and X5050 can work synergistically to upregulated the super-silencer controlled apoptotic genes, thus gave rise to antitumor effects including apoptosis, cell cycle arrest and tumor growth inhibition. Overall, our data demonstrated the first example of “super-silencer” and showed that combinational usage of GSK343 and X5050 maybe the potential drug to curing cancers through disruption of “super-silencers”.

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Project description:Human silencers have been shown to exist and 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, through interrogating two putative silencer components of FGF18 gene, we found that two nearby silencers can cooperate via compensatory chromatin interactions to form a “super-silencer”. Furthermore, double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To perturb the “super-silencers”, we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 (“GR”). We found that GR led to severe loss of TADs and loops, while the use of one inhibitor by itself only showed mild changes. Such changes in TADs and loops were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GSK343 and X5050 synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects both in vitro and in vivo. Overall, our data demonstrated the first example of a “super-silencer” and showed that combinational usage of GSK343 and X5050 to disrupt “super-silencers” could potentially lead to cancer ablation.

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

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

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human genome-wide silencers

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Systematic identification of silencers in human cells

Project description:The majority of the human genome does not encode proteins. Many of these noncoding regions contain important regulatory sequences that control gene expression. To date, most studies have focused on activators such as enhancers, but regions that repress gene expression⎯silencers⎯have not been systematically studied. We have developed a system that identifies silencer regions in a genome-wide fashion based on silencer-mediated transcriptional repression of caspase 9. We found that silencers are widely distributed and may function in a tissue-specific fashion. These silencers harbor unique epigenetic signatures and are associated with specific transcription factors. Silencers also act at multiple genes, and at the level of chromosomal domains and long-range interactions. Deletion of silencer regions linked to the drug transporter genes ABCC2 and ABCG2 caused chemo-resistance. Overall, our study demonstrates that tissue-specific silencing is widespread throughout the human genome and likely contributes significantly to the regulation of gene expression and human biology.

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