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

English version České info

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.

Vyšlo v časopise: Comparative Anatomy of Chromosomal Domains with Imprinted and Non-Imprinted Allele-Specific DNA Methylation. PLoS Genet 9(8): e32767. doi:10.1371/journal.pgen.1003622
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003622

Souhrn

Zdroje

1. TyckoB (2010) Allele-specific DNA methylation: beyond imprinting. Human Molecular Genetics 19: R210–220.

2. HarkAT, SchoenherrCJ, KatzDJ, IngramRS, LevorseJM, et al. (2000) CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405 : 486–489.

3. BellAC, FelsenfeldG (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405 : 482–485.

4. ShinJY, FitzpatrickGV, HigginsMJ (2008) Two distinct mechanisms of silencing by the KvDMR1 imprinting control region. Embo J 27 : 168–178.

5. FitzpatrickGV, PugachevaEM, ShinJY, AbdullaevZ, YangY, et al. (2007) Allele-specific binding of CTCF to the multipartite imprinting control region KvDMR1. Mol Cell Biol 27 : 2636–2647.

6. TakadaS, PaulsenM, TevendaleM, TsaiCE, KelseyG, et al. (2002) Epigenetic analysis of the Dlk1-Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2-H19. Human molecular genetics 11 : 77–86.

7. KerkelK, SpadolaA, YuanE, KosekJ, JiangL, et al. (2008) Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet 40 : 904–908.

8. TreppendahlMB, QiuX, SogaardA, YangX, Nandrup-BusC, et al. (2012) Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML. Blood 119 : 206–216.

9. FrankD, FortinoW, ClarkL, MusaloR, WangW, et al. (2002) Placental overgrowth in mice lacking the imprinted gene Ipl. Proc Natl Acad Sci U S A 99 : 7490–7495.

10. TyckoB (2006) Imprinted genes in placental growth and obstetric disorders. Cytogenet Genome Res 113 : 271–278.

11. CoanPM, BurtonGJ, Ferguson-SmithAC (2005) Imprinted genes in the placenta–a review. Placenta 26 Suppl A: S10–20.

12. WildmanDE (2011) Review: Toward an integrated evolutionary understanding of the mammalian placenta. Placenta 32 Suppl 2: S142–145.

13. GeorgiadesP, Ferguson-SmithAC, BurtonGJ (2002) Comparative developmental anatomy of the murine and human definitive placentae. Placenta 23 : 3–19.

14. RosenbloomKR, DreszerTR, LongJC, MalladiVS, SloanCA, et al. (2012) ENCODE whole-genome data in the UCSC Genome Browser: update 2012. Nucleic Acids Res 40: D912–917.

15. ChenPY, FengS, JooJW, JacobsenSE, PellegriniM (2011) A comparative analysis of DNA methylation across human embryonic stem cell lines. Genome Biol 12: R62.

16. ListerR, PelizzolaM, DowenRH, HawkinsRD, HonG, et al. (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462 : 315–322.

17. SchillingE, El ChartouniC, RehliM (2009) Allele-specific DNA methylation in mouse strains is mainly determined by cis-acting sequences. Genome Res 19 : 2028–2035.

18. LeeK, KunkeawN, JeonSH, LeeI, JohnsonBH, et al. (2011) Precursor miR-886, a novel noncoding RNA repressed in cancer, associates with PKR and modulates its activity. RNA 17 : 1076–1089.

19. SkrekaK, SchaffererS, NatIR, ZywickiM, SaltiA, et al. (2012) Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation. Nucleic Acids Res [epub ahead of print] doi: 10.1093/nar/gks311

20. RaunioH, Rahnasto-RillaM (2012) CYP2A6: genetics, structure, regulation, and function. Drug metabolism and drug interactions 27 : 73–88.

21. PelakK, GoldsteinDB, WalleyNM, FellayJ, GeD, et al. (2010) Host determinants of HIV-1 control in African Americans. The Journal of infectious diseases 201 : 1141–1149.

22. LinM, WeiLJ, SellersWR, LieberfarbM, WongWH, et al. (2004) dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 20 : 1233–1240.

23. LiLC, DahiyaR (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18 : 1427–1431.

24. KomoriHK, LaMereSA, TorkamaniA, HartGT, KotsopoulosS, et al. (2011) Application of microdroplet PCR for large-scale targeted bis-seq. Genome Res 21 : 1738–1745.