title: Comparative anatomy of chromosomal domains with imprinted and non-imprinted allele-specific DNA methylation.
abstract: Allele-specific DNA methylation (ASM) is well studied in imprinted domains, but this type of epigenetic asymmetry is actually found more commonly at non-imprinted loci, where the ASM is dictated not by parent-of-origin but instead by the local haplotype. We identified loci with strong ASM in human tissues from methylation-sensitive SNP array data. Two index regions (bisulfite PCR amplicons), one between the C3orf27 and RPN1 genes in chromosome band 3q21 and the other near the VTRNA2-1 vault RNA in band 5q31, proved to be new examples of imprinted DMRs (maternal alleles methylated) while a third, between STEAP3 and C2orf76 in chromosome band 2q14, showed non-imprinted haplotype-dependent ASM. Using long-read bisulfite sequencing (bis-seq) in 8 human tissues we found that in all 3 domains the ASM is restricted to single differentially methylated regions (DMRs), each less than 2kb. The ASM in the C3orf27-RPN1 intergenic region was placenta-specific and associated with allele-specific expression of a long non-coding RNA. Strikingly, the discrete DMRs in all 3 regions overlap with binding sites for the insulator protein CTCF, which we found selectively bound to the unmethylated allele of the STEAP3-C2orf76 DMR. Methylation mapping in two additional genes with non-imprinted haplotype-dependent ASM, ELK3 and CYP2A7, showed that the CYP2A7 DMR also overlaps a CTCF site. Thus, two features of imprinted domains, highly localized DMRs and allele-specific insulator occupancy by CTCF, can also be found in chromosomal domains with non-imprinted ASM. Arguing for biological importance, our analysis of published whole genome bis-seq data from hES cells revealed multiple genome-wide association study (GWAS) peaks near CTCF binding sites with ASM.
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Anupam
authors.initials: A
authors.lastname: Paliwal
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Temkin
authors.forename: Kristi
authors.initials: K
authors.lastname: Kerkel
authors.forename: Alexander
authors.initials: A
authors.lastname: Yale
authors.forename: Iveta
authors.initials: I
authors.lastname: Yotova
authors.forename: Natalia
authors.initials: N
authors.lastname: Drost
authors.forename: Simon
authors.initials: S
authors.lastname: Lax
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Nhan-Chang
authors.forename: Charles
authors.initials: C
authors.lastname: Powell
authors.forename: Alain
authors.initials: A
authors.lastname: Borczuk
authors.forename: Abraham
authors.initials: A
authors.lastname: Aviv
authors.forename: Ronald
authors.initials: R
authors.lastname: Wapner
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.forename: Peter L
authors.initials: PL
authors.lastname: Nagy
authors.forename: Nicholas
authors.initials: N
authors.lastname: Schork
authors.forename: Catherine
authors.initials: C
authors.lastname: Do
authors.forename: Ali
authors.initials: A
authors.lastname: Torkamani
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
mesh_terms: D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics*; D000076246:CCCTC-Binding Factor; D002875:Chromosomes / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D019175:DNA Methylation / Q000235:genetics*; D005326:Fetal Proteins / Q000235:genetics*; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006239:Haplotypes; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D062085:RNA, Long Noncoding / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000235:genetics
chemical_list: D001798:Blood Proteins; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C527883:Elk3 protein, human; D005326:Fetal Proteins; C108385:LINC01565 protein, human; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D014157:Transcription Factors; D001189:Aryl Hydrocarbon Hydroxylases; C423964:CYP2A7 protein, human; D000072467:Cytochrome P450 Family 2