Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci

To assess the impact of genetic variation in regulatory loci on human health, we constructed a high-resolution map of allelic imbalances in DNA methylation, histone marks, and gene transcription in 71 epigenomes from 36 distinct cell and tissue types from 13 donors. Deep whole-genome bisulfite seque...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2018-09, Vol.361 (6409)
Main Authors: Onuchic, Vitor, Lurie, Eugene, Carrero, Ivenise, Pawliczek, Piotr, Patel, Ronak Y, Rozowsky, Joel, Galeev, Timur, Huang, Zhuoyi, Altshuler, Robert C, Zhang, Zhizhuo, Harris, R Alan, Coarfa, Cristian, Ashmore, Lillian, Bertol, Jessica W, Fakhouri, Walid D, Yu, Fuli, Kellis, Manolis, Gerstein, Mark, Milosavljevic, Aleksandar
Format: Article
Language:English
Subjects:
Alleles
Allelic Imbalance
Binding Sites
Biological evolution
Bisulfite
Buffers
Chromosomes
Circuits
CpG Islands
Deoxyribonucleic acid
Disease - genetics
DNA
DNA Methylation
Donors
Epigenesis, Genetic
Gene expression
Gene mapping
Gene regulation
Gene Regulatory Networks
Gene sequencing
Genes
Genetic diversity
Genetic Loci
Genetic variance
Genetics
Genome, Human
Genome-Wide Association Study
Genomes
Homology
Humans
Innovations
Loci
Mutation
Nucleotide sequence
Polymorphism, Single Nucleotide
Regulatory sequences
Sensitivity
Sequence Analysis, DNA
Stochasticity
Sulfites - chemistry
Switches
Switching
Transcription factors
Transcription Factors - metabolism
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Summary:To assess the impact of genetic variation in regulatory loci on human health, we constructed a high-resolution map of allelic imbalances in DNA methylation, histone marks, and gene transcription in 71 epigenomes from 36 distinct cell and tissue types from 13 donors. Deep whole-genome bisulfite sequencing of 49 methylomes revealed sequence-dependent CpG methylation imbalances at thousands of heterozygous regulatory loci. Such loci are enriched for stochastic switching, which is defined as random transitions between fully methylated and unmethylated states of DNA. The methylation imbalances at thousands of loci are explainable by different relative frequencies of the methylated and unmethylated states for the two alleles. Further analyses provided a unifying model that links sequence-dependent allelic imbalances of the epigenome, stochastic switching at gene regulatory loci, and disease-associated genetic variation.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aar3146