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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276133 | GEO | 2025/02/28

REPOSITORIES: GEO

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

Project description: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.

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Epigenetic signatures of alcohol abuse and hepatitis infection during hepatocarcinogenesis

Project description:Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Altered DNA methylation landscapes are ubiquitous features of cancer. Interpretation of epigenetic aberrations in HCC is confounded by effects of multiple etiologic drivers and underlying cirrhosis in most cases. We globally profiled the DNA methylome of 34 normal livers and 122 primary liver disease tissues arising in the setting of chronic hepatitis B (HBV) or C (HCV) viral infection, alcoholism (EtOH), and other causes to examine how these environmental agents impact DNA methylation in a manner that contributes to liver disease. Our results demonstrate that each etiologic factor leaves unique and overlapping signatures on the DNA methylome. CpGs aberrantly methylated in cirrhosis-HCV and conserved in HCC were enriched for cancer driver genes, suggesting a pathogenic role for HCV-induced methylation changes. Additionally, large genomic regions displaying stepwise hypermethylation or hypomethylation during disease progression were identified. HCC-HCV/EtOH methylomes overlap highly with cryptogenic HCC, suggesting shared epigenetically deregulated pathways for hepatic carcinogenesis. Finally, overlapping methylation abnormalities between primary and cultured tumors unveil highly conserved epigenetic signatures in HCC. Taken together, this study characterizes progressive liver DNA methylome changes under exposure to detrimental environmental agents and illuminates possible biomarkers for early detection of HCC. 156 primary tissues and 25 cultured normal and HCC cell lines

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Dnmt1 has de novo activity targeted to transposable elements

Project description:DNA methylation plays a critical role in development, particularly in repressing retrotransposons. The mammalian methylation landscape is dependent on the combined activities of the canonical maintenance enzyme Dnmt1 and the de novo Dnmts, 3a and 3b. Here we demonstrate that Dnmt1 displays de novo methylation activity in vitro and in vivo with specific retrotransposon targeting. We used whole-genome bisulfite and long-read Nanopore sequencing in genetically engineered methylation depleted embryonic stem cells to provide an in-depth assessment and quantification of this activity. Utilizing additional knockout lines and molecular characterization, we show that Dnmt1's de novo methylation activity depends on Uhrf1 and its genomic recruitment overlaps with targets that enrich for Trim28 and H3K9 trimethylation. Our data demonstrate that Dnmt1 can de novo add and maintain DNA methylation, especially at retrotransposons and that this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development.

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