Biology subjects

Leung, D. C. Y.

Publications and source records attributed to Leung, D. C. Y..

3 recordsLinked to original sources

bioRxiv2024

Epigenomic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potentials

Hepatocellular carcinoma (HCC) exhibits widespread epigenetic alterations, yet their impact on cis-regulatory elements (CREs) and retrotransposons remains poorly understood. Here, we present an integrated epigenomic and transcriptomic analysis of HCC tumors and matched tumor-adjacent normal tissues. We identified extensive DNA hypomethylation coupled with changes in histone modifications at partially methylated domains, CREs, and retrotransposons. These epigenetic aberrations were associated with dysregulated expression of genes involved in cell cycle regulation, immune response, and extracellular matrix organization. Notably, our findings revealed a novel mechanism for the transcriptional dysregulation of GPC3, a key HCC biomarker and immunotherapeutic target. We observed that GPC3 upregulation is driven by both the reactivation of a fetal liver super enhancer and hypomethylation of GPC3-associated CpG islands. Moreover, we found that DNA hypomethylation-driven aberrant expression of retrotransposons carries prognostic significance in HCC. Patients with high expression of a long non-coding RNA driven by a HERVE-int element exhibited more aggressive tumors, poorer clinical outcomes, and molecular features associated with favorable immunotherapy response. Together, our study provides a comprehensive resource for understanding the role of epigenetic dysregulation in HCC and identifies retrotransposon-associated transcripts as potential biomarkers.

genomics↗

bioRxiv2022

Regulatory roles of three-dimensional structures of topologically associating domains

1Transcriptional enhancers usually, but not always, regulate genes within the same topologically associating domain (TAD). We hypothesize that this incomplete insulation is due to three-dimensional structures of corresponding chromatin domains in individual cells: Whereas enhancers and genes buried inside the "core" of a domain interact mostly with other regions in the same domain, those on the "surface" can more easily interact with the outside. Here we show that a simple measure, the intra-TAD ratio, can quantify the "coreness" of a region with respect to single-cell domains it belongs. We show that domain surfaces are permissive for high gene expression, and cell type-specific active cis-regulatory elements (CREs), active histone marks, and transcription factor binding sites are enriched on domain surfaces, most strongly in chromatin subcompartments typically considered inactive. These findings suggest a "domain surface CRE" model of gene regulation. We also find that disease-associated non-coding variants are enriched on domain surfaces.

bioinformatics↗

bioRxiv2022

SARS-CoV-2 impacts the transcriptome and epigenome at the maternal-fetal interface in pregnancy

During pregnancy, the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent works show increased incidences of adverse pregnancy outcomes in COVID-19 patients; however, the mechanism remains unclear. Here, we analyzed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from COVID-19 patients and control samples, we discovered aberrant immune activation and angiogenesis patterns in patients. Surprisingly, retrotransposons were dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced significant changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications. One-Sentence SummaryPregnant COVID-19 patients show placental epigenetic and transcriptional changes, associated with adverse pregnancy outcomes.

genomics↗