Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitors
ABSTRACT CTR9 is the scaffold subunit in Paf1c, a multifunctional complex regulating multiple steps of RNA Pol II-mediated transcription. Using inducible and stable CTR9 knockdown breast cancer cell lines, we discovered that the expression of a subset of KDMs, including KDM6A and Jarid2, is strictly controlled by CTR9. Global analyses of histone modifications revealed a significant increase of H3K27me3 upon loss of CTR9. Loss of CTR9 results in a decrease of H3K4me3 and H3K36me3 in gene bodies, and elevated levels and genome-wide expansion of H3K27me3. Mechanistically, CTR9 depletion triggers a PRC2 subtype switching from PRC2.2 to PRC2.1. As a consequence, CTR9 depletion generates vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic distribution, provide a unique mechanism of transition from transcriptionally active to repressive chromatin states and sheds light on the biological functions of CTR9 in development and cancer..
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 16. Feb. Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chan, Ngai Ting [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2020.01.08.898577 |
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| 245 | 1 | 0 | |a Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitors |
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| 520 | |a ABSTRACT CTR9 is the scaffold subunit in Paf1c, a multifunctional complex regulating multiple steps of RNA Pol II-mediated transcription. Using inducible and stable CTR9 knockdown breast cancer cell lines, we discovered that the expression of a subset of KDMs, including KDM6A and Jarid2, is strictly controlled by CTR9. Global analyses of histone modifications revealed a significant increase of H3K27me3 upon loss of CTR9. Loss of CTR9 results in a decrease of H3K4me3 and H3K36me3 in gene bodies, and elevated levels and genome-wide expansion of H3K27me3. Mechanistically, CTR9 depletion triggers a PRC2 subtype switching from PRC2.2 to PRC2.1. As a consequence, CTR9 depletion generates vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic distribution, provide a unique mechanism of transition from transcriptionally active to repressive chromatin states and sheds light on the biological functions of CTR9 in development and cancer. | ||
| 700 | 1 | |a Liu, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Junfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yidan |e verfasserin |4 aut | |
| 700 | 1 | |a Ong, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Lingjun |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Wei |e verfasserin |4 aut | |
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