Genome-wide quantification of the effects of DNA methylation on human gene regulation

Changes in DNA methylation are involved in development, disease, and the response to environmental conditions. However, not all regulatory elements are functionally methylation-dependent (MD). Here, we report a method, mSTARR-seq, that assesses the causal effects of DNA methylation on regulatory act...

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Published ineLife Vol. 7
Main Authors Lea, Amanda J, Vockley, Christopher M, Johnston, Rachel A, Del Carpio, Christina A, Barreiro, Luis B, Reddy, Timothy E, Tung, Jenny
Format Journal Article
LanguageEnglish
Published England eLife Sciences Publications Ltd 21.12.2018
eLife Sciences Publications, Ltd
Subjects
Bioinformatics
Biology
Chromatin
CpG islands
Demethylation
Deoxyribonucleic acid
DNA
DNA methylation
Environmental conditions
epigenomics
Gene expression
Gene regulation
Genetics and Genomics
Genomes
high-throughput reporter assay
Medical research
Nucleotide sequence
Proteins
Regulatory sequences
Tools and Resources
Transcription factors
North Carolina
United States > US
DNA methylation
epigenomics
genomics
genetics
high-throughput reporter assay
human
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Summary:Changes in DNA methylation are involved in development, disease, and the response to environmental conditions. However, not all regulatory elements are functionally methylation-dependent (MD). Here, we report a method, mSTARR-seq, that assesses the causal effects of DNA methylation on regulatory activity at hundreds of thousands of fragments (millions of CpG sites) simultaneously. Using mSTARR-seq, we identify thousands of MD regulatory elements in the human genome. MD activity is partially predictable using sequence and chromatin state information, and distinct transcription factors are associated with higher activity in unmethylated versus methylated DNA. Further, pioneer TFs linked to higher activity in the methylated state appear to drive demethylation of experimentally methylated sites. MD regulatory elements also predict methylation-gene expression relationships across individuals, where they are 1.6x enriched among sites with strong negative correlations. mSTARR-seq thus provides a map of MD regulatory activity in the human genome and facilitates interpretation of differential methylation studies.
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Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, United States.
Broad Institute of MIT and Harvard, Cambridge, United States.
Lewis-Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton, United States.
Department of Ecology and Evolutionary Biology, University of California, Los Angeles, United States.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.37513