Oncogenic reactivation of young L1s is a hallmark of colon cancer

Neu, D.; Hung, S.; Bartels, C. F.; Faber, Z. J.; Lovrenert, K.; Pontius, W. D.; Morgan, L.; Chakraborty, M.; Liao, W.; Chin, D.; Hong, E. S.; Gray, J.; Moreno, V.; Kalady, M.; Peters, U.; Gryder, B.; Sallari, R. C.; Scacheri, P. C.

doi:10.1101/2023.05.17.541189

bioRxiv · 10.1101/2023.05.17.541189

Oncogenic reactivation of young L1s is a hallmark of colon cancer

Neu, D.·Hung, S.·Bartels, C. F.·Faber, Z. J.·Lovrenert, K.·Pontius, W. D.·Morgan, L.·Chakraborty, M.·Liao, W.·Chin, D.·Hong, E. S.·Gray, J.·Moreno, V.·Kalady, M.·Peters, U.·Gryder, B.·Sallari, R. C.·Scacheri, P. C.

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Abstract

Transposable elements become increasingly active in both cancerous and aging cells, driven by loss of DNA methylation as cells divide. Here we leverage the epigenomes of colon cancers with matched adjacent tissue, in addition to non-cancerous normals and cell line models, to assess the role of transposable elements as drivers or passengers in cancer development. Using the baseline of activity from normal and adjacent tissue, we show that the youngest subfamilies of the LINE1 (L1) family exhibit a degree of activity and recurrence across patients that goes beyond what is expected from hypomethylation and cell division, suggesting an additional mechanism of oncogenic reactivation. We characterize this mechanism and find that the loss of the tumor suppressor PLZF drives young L1 reactivation in a cell-division-independent manner. PLZF de-repression exposes abundant motifs for tumor core factors in the L1 5UTR. Active young L1s act as oncogenic enhancers, interacting with oncogenes via gained chromatin loops. We uncover oncogenic L1 reactivation as a hallmark of colon cancer, where young L1s activate universally in our cohort at high levels of recurrence, act as enhancers to oncogenes, and become wired into the core regulatory circuitry of colon cancer.

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Neu, D., Hung, S., Bartels, C. F., Faber, Z. J., Lovrenert, K., Pontius, W. D., Morgan, L., Chakraborty, M., Liao, W., Chin, D., Hong, E. S., Gray, J., Moreno, V., Kalady, M., Peters, U., Gryder, B., Sallari, R. C., Scacheri, P. C.. 2023-05-21. Oncogenic reactivation of young L1s is a hallmark of colon cancer. https://doi.org/10.1101/2023.05.17.541189

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