An integrated -omics analysis of the epigenetic landscape of gene expression in human blood cells

• Type of Material: Article
• Authors: Elizabeth M. Kennedy, Emory University; George N. Goehring, Emory University; Michael H. Nichols, Emory University; Chloe Robins, Emory University; Divya Mehta, Queensland University of Technology; Torsten Klengel, Harvard Med Sch; Eleazar Eskin, University of California Los Angeles; Alicia K Smith, Emory University; Karen N Conneely, Emory University
• Language: English
• Date: 2018-06-19
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2018
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12864-018-4842-3
• Title of Journal or Parent Work: BMC Genomics
• ISSN: 1471-2164
• Volume: 19
• Issue: 1
• Start Page: 476
• End Page: 476
• Grant/Funding Information: Most analyses were run on Emory’s high-powered computing cluster, which was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award UL1TR000454.; EMK received support from BWF training grant ID 1008188 and the NIH National Institute of General Medical Sciences (T32GM008490).
• Keywords: PATHWAYS; Transcriptional regulation; CANCER; Life Sciences & Biomedicine; Blood cells; LEUKOCYTE DNA METHYLATION; SIGNATURES; EPIGENOME-WIDE ASSOCIATION; DNA methylation; BODY METHYLATION; DISCOVERY; HUMAN GENOME; Biotechnology & Applied Microbiology; PROMOTERS; Science & Technology; TISSUES; Genetics & Heredity; Gene expression
• Research Categories: Biology, Genetics; Biology, General

Abstract

Background: Gene expression can be influenced by DNA methylation 1) distally, at regulatory elements such as enhancers, as well as 2) proximally, at promoters. Our current understanding of the influence of distal DNA methylation changes on gene expression patterns is incomplete. Here, we characterize genome-wide methylation and expression patterns for ~ 13 k genes to explore how DNA methylation interacts with gene expression, throughout the genome. Results: We used a linear mixed model framework to assess the correlation of DNA methylation at ~ 400 k CpGs with gene expression changes at ~ 13 k transcripts in two independent datasets from human blood cells. Among CpGs at which methylation significantly associates with transcription (eCpGs), > 50% are distal (> 50 kb) or trans (different chromosome) to the correlated gene. Many eCpG-transcript pairs are consistent between studies and ~ 90% of neighboring eCpGs associate with the same gene, within studies. We find that enhancers (P < 5e-18) and microRNA genes (P = 9e-3) are overrepresented among trans eCpGs, and insulators and long intergenic non-coding RNAs are enriched among cis and distal eCpGs. Intragenic-eCpG-transcript correlations are negative in 60-70% of occurrences and are enriched for annotated gene promoters and enhancers (P < 0.002), highlighting the importance of intragenic regulation. Gene Ontology analysis indicates that trans eCpGs are enriched for transcription factor genes and chromatin modifiers, suggesting that some trans eCpGs represent the influence of gene networks and higher-order transcriptional control. Conclusions: This work sheds new light on the interplay between epigenetic changes and gene expression, and provides useful data for mining biologically-relevant results from epigenome-wide association studies.