Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment
Matt J Silver, Noah J Kessler, Branwen J Hennig, Paula Dominguez-Salas, Eleonora Laritsky, Maria S Baker, Cristian Coarfa, Hector Hernandez-Vargas, Jovita M Castelino, Michael N Routledge, Yun Yun Gong, Zdenko Herceg, Yong Sun Lee, Kwanbok Lee, Sophie E Moore, Anthony J Fulford, Andrew M Prentice, Robert A Waterland, Matt J Silver, Noah J Kessler, Branwen J Hennig, Paula Dominguez-Salas, Eleonora Laritsky, Maria S Baker, Cristian Coarfa, Hector Hernandez-Vargas, Jovita M Castelino, Michael N Routledge, Yun Yun Gong, Zdenko Herceg, Yong Sun Lee, Kwanbok Lee, Sophie E Moore, Anthony J Fulford, Andrew M Prentice, Robert A Waterland
Abstract
Background: Interindividual epigenetic variation that occurs systemically must be established prior to gastrulation in the very early embryo and, because it is systemic, can be assessed in easily biopsiable tissues. We employ two independent genome-wide approaches to search for such variants.
Results: First, we screen for metastable epialleles by performing genomewide bisulfite sequencing in peripheral blood lymphocyte (PBL) and hair follicle DNA from two Caucasian adults. Second, we conduct a genomewide screen for genomic regions at which PBL DNA methylation is affected by season of conception in rural Gambia. Remarkably, both approaches identify the genomically imprinted VTRNA2-1 as a top environmentally responsive epiallele. We demonstrate systemic and stochastic interindividual variation in DNA methylation at the VTRNA2-1 differentially methylated region in healthy Caucasian and Asian adults and show, in rural Gambians, that periconceptional environment affects offspring VTRNA2-1 epigenotype, which is stable over at least 10 years. This unbiased screen also identifies over 100 additional candidate metastable epialleles, and shows that these are associated with cis genomic features including transposable elements.
Conclusions: The non-coding VTRNA2-1 transcript (also called nc886) is a putative tumor suppressor and modulator of innate immunity. Thus, these data indicating environmentally induced loss of imprinting at VTRNA2-1 constitute a plausible causal pathway linking early embryonic environment, epigenetic alteration, and human disease. More broadly, the list of candidate metastable epialleles provides a resource for future studies of epigenetic variation and human disease.
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References
- Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33:245–54. doi: 10.1038/ng1089.
- Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol. 2009;5:401–8. doi: 10.1038/nrendo.2009.102.
- Ng JW, Barrett LM, Wong A, Kuh D, Smith GD, Relton CL. The role of longitudinal cohort studies in epigenetic epidemiology: challenges and opportunities. Genome Biol. 2012;13:246. doi: 10.1186/gb4029.
- Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13:97–109.
- Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8:253–62. doi: 10.1038/nrg2045.
- Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295–304. doi: 10.1038/nrg2540.
- Rakyan VK, Down TA, Balding DJ, Beck S. Epigenome-wide association studies for common human diseases. Nat Rev Genet. 2011;12:529–41. doi: 10.1038/nrg3000.
- Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr. 2007;27:363–88. doi: 10.1146/annurev.nutr.27.061406.093705.
- Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E. Metastable epialleles in mammals. Trends Genet. 2002;18:348–51. doi: 10.1016/S0168-9525(02)02709-9.
- Dominguez-Salas P, Moore SE, Baker MS, Bergen AW, Cox SE, Dyer RA, et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun. 2014;5:3746. doi: 10.1038/ncomms4746.
- Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, Tahiliani KG. Maternal methyl supplements increase offspring DNA methylation at Axin fused. Genesis. 2006;44:401–6. doi: 10.1002/dvg.20230.
- Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293–300. doi: 10.1128/MCB.23.15.5293-5300.2003.
- Dominguez-Salas P, Moore SE, Cole D, da Costa KA, Cox SE, Dyer RA, et al. DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr. 2013;97:1217–27. doi: 10.3945/ajcn.112.048462.
- Treppendahl MB, Qiu X, Sogaard A, Yang X, Nandrup-Bus C, Hother C, et al. Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML. Blood. 2012;119:206–16. doi: 10.1182/blood-2011-06-362541.
- Cao J, Song Y, Bi N, Shen J, Liu W, Fan J, et al. DNA methylation-mediated repression of miR-886-3p predicts poor outcome of human small cell lung cancer. Cancer Res. 2013;73:3326–35. doi: 10.1158/0008-5472.CAN-12-3055.
- Lee HS, Lee K, Jang HJ, Lee GK, Park JL, Kim SY, et al. Epigenetic silencing of the non-coding RNA nc886 provokes oncogenes during human esophageal tumorigenesis. Oncotarget. 2014;5:3472–81.
- Paliwal A, Temkin AM, Kerkel K, Yale A, Yotova I, Drost N, et al. Comparative anatomy of chromosomal domains with imprinted and non-imprinted allele-specific DNA methylation. PLoS Genet. 2013;9 doi: 10.1371/journal.pgen.1003622.
- Romanelli V, Nakabayashi K, Vizoso M, Moran S, Iglesias-Platas I, Sugahara N, et al. Variable maternal methylation overlapping the nc886/vtRNA2-1 locus is locked between hypermethylated repeats and is frequently altered in cancer. Epigenetics. 2014;9:783–90. doi: 10.4161/epi.28323.
- Moore SE, Cole TJ, Poskitt EM, Sonko BJ, Whitehead RG, McGregor IA, et al. Season of birth predicts mortality in rural Gambia. Nature. 1997;388:434. doi: 10.1038/41245.
- Waterland RA, Kellermayer R, Laritsky E, Rayco-Solon P, Harris RA, Travisano M, et al. Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 2010;6 doi: 10.1371/journal.pgen.1001252.
- Kunde-Ramamoorthy G, Coarfa C, Laritsky E, Kessler NJ, Harris RA, Xu M, et al. Comparison and quantitative verification of mapping algorithms for whole-genome bisulfite sequencing. Nucleic Acids Res. 2014;42 doi: 10.1093/nar/gkt1325.
- Adams D, Altucci L, Antonarakis SE, Ballesteros J, Beck S, Bird A, Bock C, Boehm B, Campo E, Caricasole A, et al: BLUEPRINT to decode the epigenetic signature written in blood. Nat Biotechnol. 2012;30:224-226.
- Zhang X, Moen EL, Liu C, Mu W, Gamazon ER, Delaney SM, et al. Linking the genetic architecture of cytosine modifications with human complex traits. Hum Mol Genet. 2014;23:5893–905. doi: 10.1093/hmg/ddu313.
- Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le JM, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011;98:288–95. doi: 10.1016/j.ygeno.2011.07.007.
- Michels KB, Binder AM, Dedeurwaerder S, Epstein CB, Greally JM, Gut I, et al. Recommendations for the design and analysis of epigenome-wide association studies. Nat Methods. 2013;10:949–55. doi: 10.1038/nmeth.2632.
- Jaffe AE, Murakami P, Lee H, Leek JT, Fallin MD, Feinberg AP, et al. Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. Int J Epidemiol. 2012;41:200–9. doi: 10.1093/ije/dyr238.
- Jaffe AE, Irizarry RA. Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 2014;15:R31. doi: 10.1186/gb-2014-15-2-r31.
- Oakes CC, Claus R, Gu L, Assenov Y, Hullein J, Zucknick M, et al. Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer Discov. 2014;4:348–61. doi: 10.1158/-13-0349.
- Gemma C, Ramagopalan SV, Down TA, Beyan H, Hawa MI, Holland ML, et al. Inactive or moderately active human promoters are enriched for inter-individual epialleles. Genome Biol. 2013;14:R43. doi: 10.1186/gb-2013-14-5-r43.
- Lou S, Lee HM, Qin H, Li JW, Gao Z, Liu X, et al. Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation. Genome Biol. 2014;15:408. doi: 10.1186/s13059-014-0408-0.
- Slotkin RK, Martienssen R. Transposable elements and the epigenetic regulation of the genome. Nat Rev Genet. 2007;8:272–85. doi: 10.1038/nrg2072.
- Harris RA, Nagy-Szakal D, Kellermayer R. Human metastable epiallele candidates link to common disorders. Epigenetics. 2013;8:157–63. doi: 10.4161/epi.23438.
- Li X, Ito M, Zhou F, Youngson N, Zuo X, Leder P, et al. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev Cell. 2008;15:547–57. doi: 10.1016/j.devcel.2008.08.014.
- Amarasekera M, Martino D, Ashley S, Harb H, Kesper D, Strickland D, et al. Genome-wide DNA methylation profiling identifies a folate-sensitive region of differential methylation upstream of ZFP57-imprinting regulator in humans. FASEB J. 2014;28:4068–4076. doi: 10.1096/fj.13-249029.
- Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr. 1999;69:179–97.
- Lee K, Kunkeaw N, Jeon SH, Lee I, Johnson BH, Kang GY, et al. Precursor miR-886, a novel noncoding RNA repressed in cancer, associates with PKR and modulates its activity. RNA. 2011;17:1076–89. doi: 10.1261/rna.2701111.
- Moore SE, Cole TJ, Collinson AC, Poskitt EM, McGregor IA, Prentice AM. Prenatal or early postnatal events predict infectious deaths in young adulthood in rural Africa. Int J Epidemiol. 1999;28:1088–95. doi: 10.1093/ije/28.6.1088.
- Krueger F, Andrews SR. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011;27:1571–2. doi: 10.1093/bioinformatics/btr167.
- Liu Y, Siegmund KD, Laird PW, Berman BP. Bis-SNP: Combined DNA methylation and SNP calling for Bisulfite-seq data. Genome Biol. 2012;13:R61. doi: 10.1186/gb-2012-13-7-r61.
- Shen L, Guo Y, Chen X, Ahmed S, Issa JP. Optimizing annealing temperature overcomes bias in bisulfite PCR methylation analysis. Biotechniques. 2007;42:48–58. doi: 10.2144/000112312.
- Harris RA, Wang T, Coarfa C, Nagarajan RP, Hong C, Downey SL, et al. Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nat Biotechnol. 2010;28:1097–105. doi: 10.1038/nbt.1682.
- Marabita F, Almgren M, Lindholm ME, Ruhrmann S, Fagerstrom-Billai F, Jagodic M, et al. An evaluation of analysis pipelines for DNA methylation profiling using the Illumina HumanMethylation450 BeadChip platform. Epigenetics. 2013;8:333–46. doi: 10.4161/epi.24008.
- Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450k DNA methylation data. Bioinformatics. 2013;29:189–96. doi: 10.1093/bioinformatics/bts680.
- Leek JT, Scharpf RB, Bravo HC, Simcha D, Langmead B, Johnson WE, et al. Tackling the widespread and critical impact of batch effects in high-throughput data. Nat Rev Genet. 2010;11:733–9. doi: 10.1038/nrg2825.
- Roessler J, Ammerpohl O, Gutwein J, Hasemeier B, Anwar SL, Kreipe H, et al. Quantitative cross-validation and content analysis of the 450k DNA methylation array from Illumina. Inc BMC Res Notes. 2012;5:210. doi: 10.1186/1756-0500-5-210.
- 1000 Genomes Project. .
- 47.Bioconductor bumphunter reference manual. . .
- Du P, Zhang X, Huang CC, Jafari N, Kibbe WA, Hou L, et al. Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics. 2010;11:587. doi: 10.1186/1471-2105-11-587.
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