Integrative epigenomic profiling of hepatocellular carcinoma uncovers aberrant cis-regulatory changes and potential prognostic indicators [ChIP-seq]

Hepatocellular carcinoma (HCC) exhibits widespread epigenetic aberrations; however, the underlying transcriptional regulatory landscape remains underexplored. Here, we performed integrated analyses with genome-wide profiles of the transcriptomes, histone modifications and DNA methylation from patient-derived HCC tumors and controls. We identified both global and focal epigenetic alterations including large-scale DNA methylation loss, and dysregulation of cis-regulatory elements (CREs) associated with genes involved in cell cycle control, immune responses, and extracellular matrix organization. Notably, we discovered that transcriptional upregulation of Glypican-3 (GPC3), a diagnostic biomarker and immunotherapeutic target for HCC, was linked to the reactivation of a fetal liver super-enhancer (SE). This SE, in concert with DNA hypomethylation of two CpG islands, modulated GPC3 expression. Global DNA hypomethylation also contributed to transcriptional dysregulation of retrotransposon-derived CREs. Specifically, we observed that patients with high expression of a HERVE-int-driven long non-coding RNA transcript showed poorer disease outcomes and specific molecular signatures associated with better response to immunotherapy. Our results highlight this and other retrotransposons as potential prognostic indicators and a predictive signature for immunotherapy response. Taken together, our findings provide insights into the role of epigenetic dysregulation of CREs and retrotransposons in hepatocarcinogenesis, which could benefit the clinical management of HCC.