DNA Sequence Explains Seemingly Disordered Methylation Levels in Partially Methylated Domains of Mammalian Genomes

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For the most part metazoan genomes are highly methylated and harbor only small regions with low or absent methylation. In contrast, partially methylated domains (PMDs), recently discovered in a variety of cell lines and tissues, do not fit this paradigm as they show partial methylation for large portions (20%–40%) of the genome. While in PMDs methylation levels are reduced on average, we found that at single CpG resolution, they show extensive variability along the genome outside of CpG islands and DNase I hypersensitive sites (DHS). Methylation levels range from 0% to 100% in a roughly uniform fashion with only little similarity between neighboring CpGs. A comparison of various PMD-containing methylomes showed that these seemingly disordered states of methylation are strongly conserved across cell types for virtually every PMD. Comparative sequence analysis suggests that DNA sequence is a major determinant of these methylation states. This is further substantiated by a purely sequence based model which can predict 31% (R²) of the variation in methylation. The model revealed CpG density as the main driving feature promoting methylation, opposite to what has been shown for CpG islands, followed by various dinucleotides immediately flanking the CpG and a minor contribution from sequence preferences reflecting nucleosome positioning. Taken together we provide a reinterpretation for the nucleotide-specific methylation levels observed in PMDs, demonstrate their conservation across tissues and suggest that they are mainly determined by specific DNA sequence features.

Vyšlo v časopise: DNA Sequence Explains Seemingly Disordered Methylation Levels in Partially Methylated Domains of Mammalian Genomes. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004143
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004143

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1. MeissnerA, MikkelsenTS, GuH, WernigM, HannaJ, et al. (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454 : 766–770.

2. IrizarryRA, Ladd-AcostaC, WenB, WuZ, MontanoC, et al. (2009) The human colon cancer methylome shows similar hypo -⁠ and hypermethylation at conserved tissue-specific CpG island shores. Nature genetics 41 : 178–186.

3. StadlerMB, MurrR, BurgerL, IvanekR, LienertF, et al. (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480 : 490–495.

4. HodgesE, MolaroA, Dos SantosCO, ThekkatP, SongQ, et al. (2011) Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Molecular cell 44 : 17–28.

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

6. ListerR, PelizzolaM, KidaYS, HawkinsRD, NeryJR, et al. (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471 : 68–73.

7. SchroederDI, LottP, KorfI, LaSalleJM (2011) Large-scale methylation domains mark a functional subset of neuronally expressed genes. Genome research 21 : 1583–1591.

8. HonGC, HawkinsRD, CaballeroOL, LoC, ListerR, et al. (2012) Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome research 22 : 246–258.

9. BermanBP, WeisenbergerDJ, AmanJF, HinoueT, RamjanZ, et al. (2012) Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nature genetics 44 : 40–46.

10. SchroederDI, BlairJD, LottP, YuHO, HongD, et al. (2013) The human placenta methylome. Proceedings of the National Academy of Sciences of the United States of America 110 : 6037–6042.

11. NephS, VierstraJ, StergachisAB, ReynoldsAP, HaugenE, et al. (2012) An expansive human regulatory lexicon encoded in transcription factor footprints. Nature 489 : 83–90.

12. HansenKD, TimpW, BravoHC, SabunciyanS, LangmeadB, et al. (2011) Increased methylation variation in epigenetic domains across cancer types. Nature genetics 43 : 768–775.

13. FeinbergAP, GehrkeCW, KuoKC, EhrlichM (1988) Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer research 48 : 1159–1161.

14. ShenL, WuLC, SanliogluS, ChenR, MendozaAR, et al. (1994) Structure and genetics of the partially duplicated gene RP located immediately upstream of the complement C4A and the C4B genes in the HLA class III region. Molecular cloning, exon-intron structure, composite retroposon, and breakpoint of gene duplication. The Journal of biological chemistry 269 : 8466–8476.

15. Strichman-AlmashanuLZ, LeeRS, OnyangoPO, PerlmanE, FlamF, et al. (2002) A genome-wide screen for normally methylated human CpG islands that can identify novel imprinted genes. Genome research 12 : 543–554.

16. OstertagEM, GoodierJL, ZhangY, KazazianHHJr (2003) SVA elements are nonautonomous retrotransposons that cause disease in humans. American journal of human genetics 73 : 1444–1451.

17. HancksDC, KazazianHHJr (2010) SVA retrotransposons: Evolution and genetic instability. Seminars in cancer biology 20 : 234–245.

18. BurgerL, GaidatzisD, SchubelerD, StadlerMB (2013) Identification of active regulatory regions from DNA methylation data. Nucleic acids research 41: e155.

19. ChodavarapuRK, FengS, BernatavichuteYV, ChenPY, StroudH, et al. (2010) Relationship between nucleosome positioning and DNA methylation. Nature 466 : 388–392.

20. ValouevA, JohnsonSM, BoydSD, SmithCL, FireAZ, et al. (2011) Determinants of nucleosome organization in primary human cells. Nature 474 : 516–520.

21. KaplanN, MooreIK, Fondufe-MittendorfY, GossettAJ, TilloD, et al. (2009) The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458 : 362–366.

22. KellyTK, LiuY, LayFD, LiangG, BermanBP, et al. (2012) Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules. Genome research 22 : 2497–2506.

23. ChungHR, DunkelI, HeiseF, LinkeC, KrobitschS, et al. (2010) The effect of micrococcal nuclease digestion on nucleosome positioning data. PloS one 5: e15754.

24. EdwardsJR, O'DonnellAH, RollinsRA, PeckhamHE, LeeC, et al. (2010) Chromatin and sequence features that define the fine and gross structure of genomic methylation patterns. Genome research 20 : 972–980.

25. BockC, PaulsenM, TierlingS, MikeskaT, LengauerT, et al. (2006) CpG island methylation in human lymphocytes is highly correlated with DNA sequence, repeats, and predicted DNA structure. PLoS genetics 2: e26.

26. RaddatzG, GaoQ, BenderS, JaenischR, LykoF (2012) Dnmt3a protects active chromosome domains against cancer-associated hypomethylation. PLoS genetics 8: e1003146.

27. BhasinM, ZhangH, ReinherzEL, RechePA (2005) Prediction of methylated CpGs in DNA sequences using a support vector machine. FEBS letters 579 : 4302–4308.

28. HandaV, JeltschA (2005) Profound flanking sequence preference of Dnmt3a and Dnmt3b mammalian DNA methyltransferases shape the human epigenome. Journal of molecular biology 348 : 1103–1112.

29. FeltusFA, LeeEK, CostelloJF, PlassC, VertinoPM (2003) Predicting aberrant CpG island methylation. Proceedings of the National Academy of Sciences of the United States of America 100 : 12253–12258.

30. BockC, WalterJ, PaulsenM, LengauerT (2007) CpG island mapping by epigenome prediction. PLoS computational biology 3: e110.

31. WrzodekC, BuchelF, HinselmannG, EichnerJ, MittagF, et al. (2012) Linking the epigenome to the genome: correlation of different features to DNA methylation of CpG islands. PloS one 7: e35327.

32. ZhengH, WuH, LiJ, JiangSW (2013) CpGIMethPred: computational model for predicting methylation status of CpG islands in human genome. BMC medical genomics 6 Suppl 1: S13.

33. XieW, BarrCL, KimA, YueF, LeeAY, et al. (2012) Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell 148 : 816–831.

34. GentlemanRC, CareyVJ, BatesDM, BolstadB, DettlingM, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome biology 5: R80.

35. LangmeadB, TrapnellC, PopM, SalzbergSL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome biology 10: R25.

36. BrykczynskaU, HisanoM, ErkekS, RamosL, OakeleyEJ, et al. (2010) Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nature structural & molecular biology 17 : 679–687.