Comparative Anatomy of Chromosomal Domains with Imprinted and Non-Imprinted Allele-Specific DNA Methylation

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. © 2013 paliwal et al.