Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels
DNA methylation is an important epigenetic mark that contributes to many biological processes including the regulation of gene expression. Genetic variation has been associated with quantitative changes in DNA methylation (meQTLs). We identified thousands of meQTLs using an assay that allowed us to measure methylation levels at around 300 thousand cytosines. We found that meQTLs are enriched with loci that is also associated with quantitative changes in gene expression, DNase I hypersensitivity, PolII occupancy, and a number of histone marks. This suggests that many molecular events are likely regulated in concert. Finally, we found that changes in transcription factor binding as well as transcription factor abundance are associated with changes in DNA methylation near transcription factor binding sites. This work contributes to our understanding of the regulation of DNA methylation in the larger context of gene regulatory landscape.
Vyšlo v časopise:
Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004663
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1004663
Souhrn
DNA methylation is an important epigenetic mark that contributes to many biological processes including the regulation of gene expression. Genetic variation has been associated with quantitative changes in DNA methylation (meQTLs). We identified thousands of meQTLs using an assay that allowed us to measure methylation levels at around 300 thousand cytosines. We found that meQTLs are enriched with loci that is also associated with quantitative changes in gene expression, DNase I hypersensitivity, PolII occupancy, and a number of histone marks. This suggests that many molecular events are likely regulated in concert. Finally, we found that changes in transcription factor binding as well as transcription factor abundance are associated with changes in DNA methylation near transcription factor binding sites. This work contributes to our understanding of the regulation of DNA methylation in the larger context of gene regulatory landscape.
Zdroje
1. StrangerBE, ForrestMS, ClarkAG, MinichielloMJ, DeutschS, et al. (2005) Genome-Wide Associations of Gene Expression Variation in Humans. PLoS Genetics 1: e78.
2. PickrellJK, MarioniJC, PaiAA, DegnerJF, EngelhardtBE, et al. (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464: 768–772.
3. StrangerBE, NicaAC, ForrestMS, BeazleyC, IngleCE, et al. (2007) Population genomics of human gene expression. Nature Genetics 39: 1217–1224.
4. HeynH, MoranS, Hernando-HerraezI, SayolsS, GomezA, et al. (2013) DNA methylation contributes to natural human variation. Genome Research 23: 1363–1372.
5. VeyrierasJ-B, DermitzakisET, GiladY, StephensM, PritchardJK (2008) High-Resolution Mapping of Expression-QTLs Yields Insight into Human Gene Regulation. PLoS Genetics 4: e1000214.
6. BrownCD, MangraviteLM, EngelhardtBE (2012) Integrative modeling of eQTLs and cis-regulatory elements suggest mechanisms underlying cell type specificity of eQTLs. arXivorg
7. GaffneyDJ, VeyrierasJ-B, DegnerJF, Pique-RegiR, PaiAA, et al. (2012) Dissecting the regulatory architecture of gene expression QTLs. Genome Biology 13: R7.
8. GibbsJR, van der BrugMP, HernandezDG, TraynorBJ, NallsMA, et al. (2010) Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain. PLoS Genetics 6: e1000952.
9. PickrellJK (2014) Joint Analysis of Functional Genomic Data and Genome-wide Association Studies of 18 Human Traits. Am J Hum Genet 94: 559–573.
10. AndersonCA, BoucherG, LeesCW, FrankeA, D'AmatoM, et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43: 246–252.
11. LappalainenT, SammethM, FriedlanderMR, t HoenPA, MonlongJ, et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501: 506–511.
12. BellJT, PaiAA, PickrellJK, GaffneyDJ, Pique-RegiR, et al. (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biology 12: R10.
13. LeeJT (2012) Epigenetic regulation by long noncoding RNAs. Science 338: 1435–1439.
14. DunhamII, KundajeAA, AldredSFSF, CollinsPJPJ, DavisCACA, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.
15. AkkersRC, van HeeringenSJ, JacobiUG, Janssen-MegensEM, FranCoijsK-J, et al. (2009) A Hierarchy of H3K4me3 and H3K27me3 Acquisition in Spatial Gene Regulation in Xenopus Embryos. Developmental Cell 17: 425–434.
16. CotneyJ, LengJ, OhS, DemareLE, ReillySK, et al. (2012) Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb. Genome Research 22: 1069–1080.
17. KasowskiM, Kyriazopoulou-PanagiotopoulouS, GrubertF, ZauggJB, KundajeA, et al. (2013) Extensive variation in chromatin states across humans. Science 342: 750–752.
18. KilpinenH, WaszakSM, GschwindAR, RaghavSK, WitwickiRM, et al. (2013) Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 342: 744–747.
19. McVickerG, van de GeijnB, DegnerJF, CainCE, BanovichNE, et al. (2013) Identification of genetic variants that affect histone modifications in human cells. Science 342: 747–749.
20. XiaoS, XieD, CaoX, YuP, XingX, et al. (2012) Comparative epigenomic annotation of regulatory DNA. Cell 149: 1381–1392.
21. DegnerJF, PaiAA, VeyrierasJ-B, GaffneyDJ, PickrellJK, et al. (2012) DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 482: 390–394.
22. HeinzS, RomanoskiCE, BennerC, AllisonKA, KaikkonenMU, et al. (2013) Effect of natural genetic variation on enhancer selection and function. Nature 503: 487–492.
23. HollidayR, PughJE (1975) DNA modification mechanisms and gene activity during development. Science 187: 226–232.
24. RiggsAD (1975) X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet 14: 9–25.
25. RiggsAD (2002) X chromosome inactivation, differentiation, and DNA methylation revisited, with a tribute to Susumu Ohno. Cytogenet Genome Res 99: 17–24.
26. RobertsonKD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20: 3139–3155.
27. BaylinSB, HermanJG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16: 168–174.
28. MendelsohnAR, LarrickJW (2013) The DNA methylome as a biomarker for epigenetic instability and human aging. Rejuvenation Res 16: 74–77.
29. IrierHA, JinP (2012) Dynamics of DNA methylation in aging and Alzheimer's disease. DNA Cell Biol 31 Suppl 1: S42–48.
30. MastroeniD, GroverA, DelvauxE, WhitesideC, ColemanPD, et al. (2010) Epigenetic changes in Alzheimer's disease: decrements in DNA methylation. Neurobiol Aging 31: 2025–2037.
31. GamazonER, BadnerJA, ChengL, ZhangC, ZhangD, et al. (2012) Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Molecular Psychiatry 18: 340–346.
32. ListerR, PelizzolaM, DowenRH, HawkinsRD, HonG, et al. (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462: 315–322.
33. WeberM, HellmannI, StadlerMB, RamosL, PääboS, et al. (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genetics 39: 457–466.
34. StadlerMB, MurrR, BurgerL, IvanekR, LienertF, et al. (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480: 490–495.
35. BirdAP (1987) CpG islands as gene markers in the vertebrate nucleus. Trends in Genetics
36. Gardiner-GardenM, FrommerM (1987) CpG islands in vertebrate genomes. Journal of molecular biology 196: 261–282.
37. ThurmanRE, RynesE, HumbertR, VierstraJ, MauranoMT, et al. (2012) The accessible chromatin landscape of the human genome. Nature 489: 75–82.
38. DrongAW, NicholsonG, HedmanAK, MeduriE, GrundbergE, et al. (2013) The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue. PLoS One 8: e55923.
39. ZhangD, ChengL, BadnerJA, ChenC, ChenQ, et al. (2010) Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet 86: 411–419.
40. Gutierrez-ArcelusM, LappalainenT, MontgomerySB, BuilA, OngenH, et al. (2013) Passive and active DNA methylation and the interplay with genetic variation in gene regulation. eLife 2: e00523.
41. ThomsonJP, SkenePJ, SelfridgeJ, ClouaireT, GuyJ, et al. (2010) CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 464: 1082–1086.
42. LindrothAM, ParkYJ, McLeanCM, DokshinGA, PerssonJM, et al. (2008) Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus. PLoS Genet 4: e1000145.
43. BrinkmanAB, GuH, BartelsSJJ, ZhangY, MatareseF, et al. (2012) Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk. Genome Research 22: 1128–1138.
44. LienertF, WirbelauerC, SomI, DeanA, MohnF, et al. (2011) Identification of genetic elements that autonomously determine DNA methylation states. Nature Genetics 43: 1091–1097.
45. ZillerMJ, GuH, MüllerF, DonagheyJ, TsaiLTY, et al. (2013) Charting a dynamic DNA methylation landscape of the human genome. Nature 500: 477–481.
46. Hernando-HerraezI, Prado-MartinezJ, GargP, Fernandez-CallejoM, HeynH, et al. (2013) Dynamics of DNA methylation in recent human and great ape evolution. PLoS Genetics 9: e1003763.
47. GrundbergE, MeduriE, SandlingJK, HedmanAK, KeildsonS, et al. (2013) Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements. The American Journal of Human Genetics 93: 876–890.
48. DurbinRM, AltshulerDL, DurbinRM, AbecasisGR, BentleyDR, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.
49. FrazerKA, BallingerDG, CoxDR, HindsDA, StuveLL, et al. (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449: 851–861.
50. ErnstJ, KheradpourP, MikkelsenTS, ShoreshN, WardLD, et al. (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473: 43–49.
51. CedarH, BergmanY (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nature Reviews Genetics 10: 295–304.
52. Pique-RegiR, DegnerJF, PaiAA, GaffneyDJ, GiladY (2011) Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome Research 21: 447–455.
53. BellJT, TsaiP-C, YangT-P, PidsleyR, NisbetJ, et al. (2012) Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genetics 8: e1002629.
54. Hindorff L, MacArthur J, Morales J, Junkins H, Hall P, et al.. (2013) A Catalog of Published Genome-Wide Association Studies. Avaiable at: http://www.genome.gov/gwastudies.
55. CaliskanM, CusanovichDA, OberC, GiladY (2011) The effects of EBV transformation on gene expression levels and methylation profiles. Human Molecular Genetics 20: 1643–1652.
56. GrafodatskayaD, ChoufaniS, FerreiraJC, ButcherDT, LouY, et al. (2010) EBV transformation and cell culturing destabilizes DNA methylation in human lymphoblastoid cell lines. Genomics 95: 73–83.
57. TatePH, BirdAP (1993) Effects of DNA methylation on DNA-binding proteins and gene expression. Current Opinion in Genetics & Development 3: 226–231.
58. HahnMA, WuX, LiAX, HahnT, PfeiferGP (2011) Relationship between Gene Body DNA Methylation and Intragenic H3K9me3 and H3K36me3 Chromatin Marks. PLoS ONE 6: e18844.
59. JonesPA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews Genetics 13: 484–492.
60. TungJ, BarreiroLB, JohnsonZP, HansenKD, MichopoulosV, et al. (2012) Social environment is associated with gene regulatory variation in the rhesus macaque immune system. Proceedings of the National Academy of Sciences [epub ahead of print] doi: 10.1073/pnas.1202734109
61. WuH, ZhangY (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes & Development 25: 2436–2452.
62. YuM, HonGC, SzulwachKE, SongC-X, ZhangL, et al. (2012) Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149: 1368–1380.
63. KruegerF (2011) Bismark, A flexible aligner and methylation caller for Bi-sulfate seqencing applications. Bioinformatics 27: 1571–2.
64. GuanY, StephensM (2008) Practical Issues in Imputation-Based Association Mapping. PLoS Genet 4: e1000279.
65. StoreyJD, TibshiraniR (2003) Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences 100: 9440–9445.
66. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.
67. Huang daW, ShermanBT, LempickiRA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37: 1–13.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2014 Číslo 9
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Admixture in Latin America: Geographic Structure, Phenotypic Diversity and Self-Perception of Ancestry Based on 7,342 Individuals
- Nipbl and Mediator Cooperatively Regulate Gene Expression to Control Limb Development
- Genome Wide Association Studies Using a New Nonparametric Model Reveal the Genetic Architecture of 17 Agronomic Traits in an Enlarged Maize Association Panel
- Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation