Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue

Clinical Epigenetics

Ramón Salazar¹  Cristina Santos²  Xavier Sanjuan³  Mireia Jordà⁴  Elisabet Guinó⁵  Rebeca Sanz-Pamplona⁵  Anna Díez-Villanueva⁵  David Cordero⁵  Robert Carreras-Torres⁵  Victor Moreno⁶  Henar Alonso⁶ 

[1] Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain;Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain;Medical Oncology Service, Catalan Institute of Oncology (ICO), Barcelona, Spain;Biomedical Research Centre Network for Oncology (CIBERONC), Madrid, Spain;Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain;Medical Oncology Service, Catalan Institute of Oncology (ICO), Barcelona, Spain;Biomedical Research Centre Network for Oncology (CIBERONC), Madrid, Spain;Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain;Pathology Department, University Hospital Bellvitge (HUB), L’Hospitalet de Llobregat, Barcelona, Spain;Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain;Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Av Gran Via 199-203, 08907, L’Hospitalet de Llobregat, Barcelona, Spain;Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain;Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Madrid, Spain;Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Av Gran Via 199-203, 08907, L’Hospitalet de Llobregat, Barcelona, Spain;Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain;Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Madrid, Spain;Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain;

关键词: DNA methylation;    Genetics;    Gene expression;    mQTLs;    eQTLs;    eQTMs;    Genetic and epigenetic control;    Epigenetic regulation;   

DOI  :  10.1186/s13148-021-01148-9

来源: Springer

【 摘 要 】

BackgroundDNA methylation is involved in the regulation of gene expression and phenotypic variation, but the inter-relationship between genetic variation, DNA methylation and gene expression remains poorly understood. Here we combine the analysis of genetic variants related to methylation markers (methylation quantitative trait loci: mQTLs) and gene expression (expression quantitative trait loci: eQTLs) with methylation markers related to gene expression (expression quantitative trait methylation: eQTMs), to provide novel insights into the genetic/epigenetic architecture of colocalizing molecular markers.ResultsNormal mucosa from 100 patients with colon cancer and 50 healthy donors included in the Colonomics project have been analyzed. Linear models have been used to find mQTLs and eQTMs within 1 Mb of the target gene. From 32,446 eQTLs previously detected, we found a total of 6850 SNPs, 114 CpGs and 52 genes interrelated, generating 13,987 significant combinations of co-occurring associations (meQTLs) after Bonferromi correction. Non-redundant meQTLs were 54, enriched in genes involved in metabolism of glucose and xenobiotics and immune system. SNPs in meQTLs were enriched in regulatory elements (enhancers and promoters) compared to random SNPs within 1 Mb of genes. Three colorectal cancer GWAS SNPs were related to methylation changes, and four SNPs were related to chemerin levels. Bayesian networks have been used to identify putative causal relationships among associated SNPs, CpG and gene expression triads. We identified that most of these combinations showed the canonical pathway of methylation markers causes gene expression variation (60.1%) or non-causal relationship between methylation and gene expression (33.9%); however, in up to 6% of these combinations, gene expression was causing variation in methylation markers.ConclusionsIn this study we provided a characterization of the regulation between genetic variants and inter-dependent methylation markers and gene expression in a set of 150 healthy colon tissue samples. This is an important finding for the understanding of molecular susceptibility on colon-related complex diseases.

【 授权许可】

CC BY