Biological Sciences Division
Published December 21, 2018 | Version v1
Journal article Open

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

Creators

  • 1. Duke University
  • 2. University of Chicago

Description

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.

Data availability

Accession numbers and links for publicly available data sets used for analyses are provided in the Methods. All sequencing data generated as part of this work are available through NCBI's Short Read Archive (SRP120556). The mSTARR-seq protocol is available online at www.tung-lab.org/protocols-and-software.html. The plasmid DNA input library described here is available on request from the authors (sequence data for the same plasmid DNA input library is available through the SRA deposit), and the pmSTARRseq1 vector is available through AddGene.

The following data sets were generated:

Amanda Lea (2018) NCBI Sequence Read Archive ID SRP120556. Genome-wide quantification of the effects of DNA methylation on human gene regulation. https://www.ncbi.nlm.nih.gov/sra/?term=SRP120556

The following previously published data sets were used:

ENCODE Project Consortium (2012) hgdownload An integrated encyclopedia of DNA elements in the human genome, wgEncodeBroadHmmK562HMM.bed.gz. http://hgdownload.cse.ucsc.edu/goldenPath/hg19/encodeDCC/wgEncodeBroadHmm/

ENCODE Project Consortium (2012) ENCODE An integrated encyclopedia of DNA elements in the human genome. https://www.encodeproject.org/experiments/ENCSR765JPC/

ENCODE Project Consortium (2012) ENCODE An integrated encyclopedia of DNA elements in the human genome. https://www.encodeproject.org/experiments/ENCSR765JPC/

Donna Karolchik Galt P. Barber Jonathan Casper Hiram Clawson Melissa S. Cline Mark Diekhans Timothy R. Dreszer Pauline A. Fujita Luvina Guruvadoo Maximilian Haeussler Rachel A. Harte Steve Heitner Angie S. Hinrichs Katrina Learned Brian T. Lee Chin H. Li Brian J. Raney Brooke Rhead Kate R. Rosenbloom Cricket A. Sloan Matthew L. Speir Ann S. Zweig David Haussler Robert M. Kuhn W. James Kent (2014) hgdownload The UCSC Genome Browser database: 2014 update, phastConsElements46wayPlacental.txt. http://hgdownload.cse.ucsc.edu/goldenPath/hg19/database/phastConsElements46wayPlacental.txt.gz

ENCODE Project Consortium (2012) hgdownload An integrated encyclopedia of DNA elements in the human genome, All K562 narrow peak files. http://hgdownload.soe.ucsc.edu/goldenPath/hg19/encodeDCC/wgEncodeAwgTfbsUniform/

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Additional details

Identifiers

DOI
10.7554/eLife.37513
Other
oai:uchicago.tind.io:9875

Funding

Alfred P. Sloan Foundation
National Institutes of Health
National Science Foundation

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine