Epigenetic dysregulation of endogenous retroviruses in hepatocellular carcinoma

Abstract

Endogenous retroviruses (ERVs) are remnants of ancestral retroviruses that serve as a rich repertoire of cis-regulatory elements in normal development and disease. While epigenetically silenced in somatic cells, ERVs could become reactivated as transcriptional enhancers and/or promoters to drive oncogenesis. Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and hepatitis B virus (HBV) infection is the leading risk factor in HCC development. Previous studies have established a link between ERV dysregulation and hepatocarcinogenesis but a comprehensive survey of the cis-regulatory activities of ERVs and their functional relevance in HCC and HBV-associated HCC (HBV-HCC) are lacking. Here, I attempted to decipher the cis-regulatory role of ERVs in HCC and HBV-HCC using multidimensional epigenomic datasets. I observed the acquisition of enhancer and/or promoter chromatin features at a subset of ERVs that in HCC and HBV-HCC. I demonstrated that specific ERV families and subfamilies gain active enhancer and/or promoter marks, suggesting activation of selected elements during hepatocarcinogenesis. Loss of histone 3 lysine 9 trimethylation (H3K9me3) and DNA methylation do not accompany the activation of candidate ERVs. The data implicate that additional regulatory factors are involved in their activation. Moreover, short-interspersed nuclear elements (SINEs), but not ERVs, preferentially gain active enhancer marks in HBV-HCC. Collectively, these findings shed light on the cis-regulatory activities of retrotransposons in hepatocarcinogenesis and the distinct regulation of ERVs in HCC and HBV-HCC.

Date of Award	2020
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology