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bioRxiv · 10.1101/2020.01.08.898577

Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitors

Xu, W.·Chan, N. T.·Liu, P.·Huang, J.·Wang, Y.·Ong, I. M.·Li, L.
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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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Xu, W., Chan, N. T., Liu, P., Huang, J., Wang, Y., Ong, I. M., Li, L.. 2020-01-08. Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitors. https://doi.org/10.1101/2020.01.08.898577

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