Cargando…
Modeling complex patterns of differential DNA methylation that associate with gene expression changes
Numerous genomic studies are underway to determine which genes are abnormally regulated by DNA methylation in disease. However, we have a poor understanding of how disease-specific methylation changes affect expression. We thus developed an integrative analysis tool, Methylation-based Gene Expressio...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435975/ https://www.ncbi.nlm.nih.gov/pubmed/28168293 http://dx.doi.org/10.1093/nar/gkx078 |
_version_ | 1783237319313063936 |
---|---|
author | Schlosberg, Christopher E. VanderKraats, Nathan D. Edwards, John R. |
author_facet | Schlosberg, Christopher E. VanderKraats, Nathan D. Edwards, John R. |
author_sort | Schlosberg, Christopher E. |
collection | PubMed |
description | Numerous genomic studies are underway to determine which genes are abnormally regulated by DNA methylation in disease. However, we have a poor understanding of how disease-specific methylation changes affect expression. We thus developed an integrative analysis tool, Methylation-based Gene Expression Classification (ME-Class), to explain specific variation in methylation that associates with expression change. This model captures the complexity of methylation changes around a gene promoter. Using 17 whole-genome bisulfite sequencing and RNA-seq datasets from different tissues from the Roadmap Epigenomics Project, ME-Class significantly outperforms standard methods using methylation to predict differential gene expression change. To demonstrate its utility, we used ME-Class to analyze 32 datasets from different hematopoietic cell types from the Blueprint Epigenome project. Expression-associated methylation changes were predominantly found when comparing cells from distantly related lineages, implying that changes in the cell's transcriptional program precede associated methylation changes. Training ME-Class on normal-tumor pairs from The Cancer Genome Atlas indicated that cancer-specific expression-associated methylation changes differ from tissue-specific changes. We further show that ME-Class can detect functionally relevant cancer-specific, expression-associated methylation changes that are reversed upon the removal of methylation. ME-Class is thus a powerful tool to identify genes that are dysregulated by DNA methylation in disease. |
format | Online Article Text |
id | pubmed-5435975 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54359752017-05-22 Modeling complex patterns of differential DNA methylation that associate with gene expression changes Schlosberg, Christopher E. VanderKraats, Nathan D. Edwards, John R. Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Numerous genomic studies are underway to determine which genes are abnormally regulated by DNA methylation in disease. However, we have a poor understanding of how disease-specific methylation changes affect expression. We thus developed an integrative analysis tool, Methylation-based Gene Expression Classification (ME-Class), to explain specific variation in methylation that associates with expression change. This model captures the complexity of methylation changes around a gene promoter. Using 17 whole-genome bisulfite sequencing and RNA-seq datasets from different tissues from the Roadmap Epigenomics Project, ME-Class significantly outperforms standard methods using methylation to predict differential gene expression change. To demonstrate its utility, we used ME-Class to analyze 32 datasets from different hematopoietic cell types from the Blueprint Epigenome project. Expression-associated methylation changes were predominantly found when comparing cells from distantly related lineages, implying that changes in the cell's transcriptional program precede associated methylation changes. Training ME-Class on normal-tumor pairs from The Cancer Genome Atlas indicated that cancer-specific expression-associated methylation changes differ from tissue-specific changes. We further show that ME-Class can detect functionally relevant cancer-specific, expression-associated methylation changes that are reversed upon the removal of methylation. ME-Class is thus a powerful tool to identify genes that are dysregulated by DNA methylation in disease. Oxford University Press 2017-05-19 2017-02-07 /pmc/articles/PMC5435975/ /pubmed/28168293 http://dx.doi.org/10.1093/nar/gkx078 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Gene regulation, Chromatin and Epigenetics Schlosberg, Christopher E. VanderKraats, Nathan D. Edwards, John R. Modeling complex patterns of differential DNA methylation that associate with gene expression changes |
title | Modeling complex patterns of differential DNA methylation that associate with gene expression changes |
title_full | Modeling complex patterns of differential DNA methylation that associate with gene expression changes |
title_fullStr | Modeling complex patterns of differential DNA methylation that associate with gene expression changes |
title_full_unstemmed | Modeling complex patterns of differential DNA methylation that associate with gene expression changes |
title_short | Modeling complex patterns of differential DNA methylation that associate with gene expression changes |
title_sort | modeling complex patterns of differential dna methylation that associate with gene expression changes |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435975/ https://www.ncbi.nlm.nih.gov/pubmed/28168293 http://dx.doi.org/10.1093/nar/gkx078 |
work_keys_str_mv | AT schlosbergchristophere modelingcomplexpatternsofdifferentialdnamethylationthatassociatewithgeneexpressionchanges AT vanderkraatsnathand modelingcomplexpatternsofdifferentialdnamethylationthatassociatewithgeneexpressionchanges AT edwardsjohnr modelingcomplexpatternsofdifferentialdnamethylationthatassociatewithgeneexpressionchanges |