title: Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment.
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.
authors.affiliation: MRC International Nutrition Group at London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. matt.silver@lshtm.ac.uk.|MRC Keneba, MRC Unit, Atlantic Boulevard, Fajara, P. O. Box 273, Banjul, The Gambia. matt.silver@lshtm.ac.uk.
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Silver
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA. Noah.Kessler@bcm.edu.
authors.forename: Noah J
authors.initials: NJ
authors.lastname: Kessler
authors.affiliation: MRC International Nutrition Group at London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. branwen.hennig@lshtm.ac.uk.|MRC Keneba, MRC Unit, Atlantic Boulevard, Fajara, P. O. Box 273, Banjul, The Gambia. branwen.hennig@lshtm.ac.uk.
authors.forename: Branwen J
authors.initials: BJ
authors.lastname: Hennig
authors.affiliation: Veterinary Epidemiology, Economics and Public Health Group, Royal Veterinary College, Hawkshead Lane, Hatfield, Hertfordshire, AL9 7TA, UK. pdominguezsalas@rvc.ac.uk.|International Livestock Research Institute, Old Naivasha Rd, Nairobi, 00100, Kenya. pdominguezsalas@rvc.ac.uk.
authors.forename: Paula
authors.initials: P
authors.lastname: Dominguez-Salas
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA. laritsky@bcm.edu.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Laritsky
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA. mstorska@bcm.edu.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Baker
authors.affiliation: Department of Molecular & Cell Biology, Baylor College of Medicine, Houston, Texas, 77030, USA. coarfa@bcm.edu.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372, Lyon, CEDEX 08, France. VargasH@iarc.fr.
authors.forename: Hector
authors.initials: H
authors.lastname: Hernandez-Vargas
authors.affiliation: School of Medicine, University of Leeds, Leeds, LS2 9JT, UK. jovitacastelino@gmail.com.
authors.forename: Jovita M
authors.initials: JM
authors.lastname: Castelino
authors.affiliation: School of Medicine, University of Leeds, Leeds, LS2 9JT, UK. medmnr@leeds.ac.uk.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Routledge
authors.affiliation: Institute for Global Food Security, Queen's University Belfast, Belfast, BT9 5AG, UK. y.gong@qub.ac.uk.
authors.forename: Yun Yun
authors.initials: YY
authors.lastname: Gong
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372, Lyon, CEDEX 08, France. HercegZ@iarc.fr.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, 77555, USA. yslee@utmb.edu.
authors.forename: Yong Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, 77555, USA. kwalee@UTMB.EDU.
authors.forename: Kwanbok
authors.initials: K
authors.lastname: Lee
authors.affiliation: MRC International Nutrition Group at London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. Sophie.Moore@mrc-hnr.cam.ac.uk.|MRC Keneba, MRC Unit, Atlantic Boulevard, Fajara, P. O. Box 273, Banjul, The Gambia. Sophie.Moore@mrc-hnr.cam.ac.uk.|MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL, UK. Sophie.Moore@mrc-hnr.cam.ac.uk.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Moore
authors.affiliation: MRC International Nutrition Group at London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. Tony.Fulford@lshtm.ac.uk.|MRC Keneba, MRC Unit, Atlantic Boulevard, Fajara, P. O. Box 273, Banjul, The Gambia. Tony.Fulford@lshtm.ac.uk.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Fulford
authors.affiliation: MRC International Nutrition Group at London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. Andrew.Prentice@lshtm.ac.uk.|MRC Keneba, MRC Unit, Atlantic Boulevard, Fajara, P. O. Box 273, Banjul, The Gambia. Andrew.Prentice@lshtm.ac.uk.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Prentice
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030, USA. waterland@bcm.edu.|Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA. waterland@bcm.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Waterland
mesh_terms: D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005714:Gambia; D018507:Gene Expression Regulation, Developmental; D016147:Genes, Tumor Suppressor; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C119570:CBLC protein, human