Cargando…

Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma

Pathologic alterations in epigenetic regulation have long been considered a hallmark of many cancers, including hepatocellular carcinoma (HCC). In a healthy individual, the relationship between DNA methylation and microRNA (miRNA) expression maintains a fine balance; however, disruptions in this har...

Descripción completa

Detalles Bibliográficos
Autores principales: Varghese, Rency S., Barefoot, Megan E., Jain, Sidharth, Chen, Yifan, Zhang, Yunxi, Alley, Amber, Kroemer, Alexander H., Tadesse, Mahlet G., Kumar, Deepak, Sherif, Zaki A., Ressom, Habtom W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453167/
https://www.ncbi.nlm.nih.gov/pubmed/34557219
http://dx.doi.org/10.3389/fgene.2021.708326
_version_ 1784570225585291264
author Varghese, Rency S.
Barefoot, Megan E.
Jain, Sidharth
Chen, Yifan
Zhang, Yunxi
Alley, Amber
Kroemer, Alexander H.
Tadesse, Mahlet G.
Kumar, Deepak
Sherif, Zaki A.
Ressom, Habtom W.
author_facet Varghese, Rency S.
Barefoot, Megan E.
Jain, Sidharth
Chen, Yifan
Zhang, Yunxi
Alley, Amber
Kroemer, Alexander H.
Tadesse, Mahlet G.
Kumar, Deepak
Sherif, Zaki A.
Ressom, Habtom W.
author_sort Varghese, Rency S.
collection PubMed
description Pathologic alterations in epigenetic regulation have long been considered a hallmark of many cancers, including hepatocellular carcinoma (HCC). In a healthy individual, the relationship between DNA methylation and microRNA (miRNA) expression maintains a fine balance; however, disruptions in this harmony can aid in the genesis of cancer or the propagation of existing cancers. The balance between DNA methylation and microRNA expression and its potential disturbance in HCC can vary by race. There is emerging evidence linking epigenetic events including DNA methylation and miRNA expression to cancer disparities. In this paper, we evaluate the epigenetic mechanisms of racial heterogenity in HCC through an integrated analysis of DNA methylation, miRNA, and combined regulation of gene expression. Specifically, we generated DNA methylation, mRNA-seq, and miRNA-seq data through the analysis of tumor and adjacent non-tumor liver tissues from African Americans (AA) and European Americans (EA) with HCC. Using mixed ANOVA, we identified cytosine-phosphate-guanine (CpG) sites, mRNAs, and miRNAs that are significantly altered in HCC vs. adjacent non-tumor tissue in a race-specific manner. We observed that the methylome was drastically changed in EA with a significantly larger number of differentially methylated and differentially expressed genes than in AA. On the other hand, the miRNA expression was altered to a larger extent in AA than in EA. Pathway analysis functionally linked epigenetic regulation in EA to processes involved in immune cell maturation, inflammation, and vascular remodeling. In contrast, cellular proliferation, metabolism, and growth pathways are found to predominate in AA as a result of this epigenetic analysis. Furthermore, through integrative analysis, we identified significantly differentially expressed genes in HCC with disparate epigenetic regulation, associated with changes in miRNA expression for AA and DNA methylation for EA.
format Online
Article
Text
id pubmed-8453167
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-84531672021-09-22 Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma Varghese, Rency S. Barefoot, Megan E. Jain, Sidharth Chen, Yifan Zhang, Yunxi Alley, Amber Kroemer, Alexander H. Tadesse, Mahlet G. Kumar, Deepak Sherif, Zaki A. Ressom, Habtom W. Front Genet Genetics Pathologic alterations in epigenetic regulation have long been considered a hallmark of many cancers, including hepatocellular carcinoma (HCC). In a healthy individual, the relationship between DNA methylation and microRNA (miRNA) expression maintains a fine balance; however, disruptions in this harmony can aid in the genesis of cancer or the propagation of existing cancers. The balance between DNA methylation and microRNA expression and its potential disturbance in HCC can vary by race. There is emerging evidence linking epigenetic events including DNA methylation and miRNA expression to cancer disparities. In this paper, we evaluate the epigenetic mechanisms of racial heterogenity in HCC through an integrated analysis of DNA methylation, miRNA, and combined regulation of gene expression. Specifically, we generated DNA methylation, mRNA-seq, and miRNA-seq data through the analysis of tumor and adjacent non-tumor liver tissues from African Americans (AA) and European Americans (EA) with HCC. Using mixed ANOVA, we identified cytosine-phosphate-guanine (CpG) sites, mRNAs, and miRNAs that are significantly altered in HCC vs. adjacent non-tumor tissue in a race-specific manner. We observed that the methylome was drastically changed in EA with a significantly larger number of differentially methylated and differentially expressed genes than in AA. On the other hand, the miRNA expression was altered to a larger extent in AA than in EA. Pathway analysis functionally linked epigenetic regulation in EA to processes involved in immune cell maturation, inflammation, and vascular remodeling. In contrast, cellular proliferation, metabolism, and growth pathways are found to predominate in AA as a result of this epigenetic analysis. Furthermore, through integrative analysis, we identified significantly differentially expressed genes in HCC with disparate epigenetic regulation, associated with changes in miRNA expression for AA and DNA methylation for EA. Frontiers Media S.A. 2021-09-07 /pmc/articles/PMC8453167/ /pubmed/34557219 http://dx.doi.org/10.3389/fgene.2021.708326 Text en Copyright © 2021 Varghese, Barefoot, Jain, Chen, Zhang, Alley, Kroemer, Tadesse, Kumar, Sherif and Ressom. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Varghese, Rency S.
Barefoot, Megan E.
Jain, Sidharth
Chen, Yifan
Zhang, Yunxi
Alley, Amber
Kroemer, Alexander H.
Tadesse, Mahlet G.
Kumar, Deepak
Sherif, Zaki A.
Ressom, Habtom W.
Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma
title Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma
title_full Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma
title_fullStr Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma
title_full_unstemmed Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma
title_short Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma
title_sort integrative analysis of dna methylation and microrna expression reveals mechanisms of racial heterogeneity in hepatocellular carcinoma
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453167/
https://www.ncbi.nlm.nih.gov/pubmed/34557219
http://dx.doi.org/10.3389/fgene.2021.708326
work_keys_str_mv AT vargheserencys integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT barefootmegane integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT jainsidharth integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT chenyifan integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT zhangyunxi integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT alleyamber integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT kroemeralexanderh integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT tadessemahletg integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT kumardeepak integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT sherifzakia integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma
AT ressomhabtomw integrativeanalysisofdnamethylationandmicrornaexpressionrevealsmechanismsofracialheterogeneityinhepatocellularcarcinoma