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

TitleAllele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci.
Publication TypeJournal Article
Year of Publication2018
AuthorsOnuchic, V, Lurie, E, Carrero, I, Pawliczek, P, Patel, RY, Rozowsky, J, Galeev, T, Huang, Z, Altshuler, RC, Zhang, Z, R Harris, A, Coarfa, C, Ashmore, L, Bertol, JW, Fakhouri, WD, Yu, F, Kellis, M, Gerstein, M, Milosavljevic, A
JournalScience
Volume361
Issue6409
Date Published2018 09 28
ISSN1095-9203
KeywordsAlleles, Allelic Imbalance, Binding Sites, CpG Islands, Disease, DNA Methylation, Epigenesis, Genetic, Gene Regulatory Networks, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Sulfites, Transcription Factors
Abstract

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.

DOI10.1126/science.aar3146
Alternate JournalScience
PubMed ID30139913
PubMed Central IDPMC6198826
Grant ListR01 HG008155 / HG / NHGRI NIH HHS / United States
R01 GM113708 / GM / NIGMS NIH HHS / United States
U01 HG007610 / HG / NHGRI NIH HHS / United States
U01 DA025956 / DA / NIDA NIH HHS / United States
R15 GM122030 / GM / NIGMS NIH HHS / United States
U54 DA036134 / DA / NIDA NIH HHS / United States
U24 HG009446 / HG / NHGRI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
R01 MH109978 / MH / NIMH NIH HHS / United States