Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Ivancevic, A.; Simpson, D. M.; Chuong, E. B.

doi:10.1101/2021.10.28.466196

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bioRxiv · 10.1101/2021.10.28.466196

Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Ivancevic, A.·Simpson, D. M.·Chuong, E. B.

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Abstract

Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the mechanisms underlying the formation of these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are a rich source of enhancers displaying cancer-specific activity. In colorectal cancer and other epithelial tumors, oncogenic AP1/MAPK signaling drives the activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements regulate tumor-specific expression of multiple genes associated with tumorigenesis, such as ATG12 and XRCC4. Within the human population, individual LTR10 elements exhibit germline and somatic structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers contribute to transcriptional dysregulation in response to oncogenic signaling and shape the evolution of cancer-specific regulatory networks.

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Ivancevic, A., Simpson, D. M., Chuong, E. B.. 2021-10-30. Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer. https://doi.org/10.1101/2021.10.28.466196

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