Comparative anatomy of chromosomal domains with imprinted and non-imprinted allele-specific DNA methylation

PLoS Genet. 2013 Aug;9(8):e1003622. doi: 10.1371/journal.pgen.1003622. Epub 2013 Aug 29.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Blood Proteins / genetics*
  • CCCTC-Binding Factor
  • Chromosomes / genetics
  • Cytochrome P450 Family 2
  • DNA Methylation / genetics*
  • Fetal Proteins / genetics*
  • Genome-Wide Association Study*
  • Genomic Imprinting*
  • Haplotypes
  • Humans
  • Oncogene Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-ets
  • RNA, Long Noncoding / genetics
  • Repressor Proteins / genetics
  • Sensitivity and Specificity
  • Transcription Factors / genetics

Substances

  • Blood Proteins
  • CCCTC-Binding Factor
  • CTCF protein, human
  • Elk3 protein, human
  • Fetal Proteins
  • LINC01565 protein, human
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • RNA, Long Noncoding
  • Repressor Proteins
  • Transcription Factors
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A7 protein, human
  • Cytochrome P450 Family 2