Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment

Authors: SILVER, MATT - London School Of Hygiene & Tropical Medicine; KESSLER, NOAH - Children'S Nutrition Research Center (CNRC); HENNIG, BRANWEN - London School Of Hygiene & Tropical Medicine; DOMINGUEZ-SALAS, PAULA - Royal Veterinary College; LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC); BAKER, MARIA - Children'S Nutrition Research Center (CNRC); COARFA, CRISTIAN - Baylor College Of Medicine; HERNANDEZ-VARGAS, HECTOR - International Agency For Research On Cancer; CASTELINO, JOVITA - University Of Leeds; ROUTLEDGE, MICHAEL - University Of Leeds; GONG, YUN YUN - Queens University - United Kingdom; HERCEG, ZDENKO - International Agency For Research On Cancer; LEE, YONG SUN - University Of Texas Medical Branch; LEE, KWANBOK - University Of Texas Medical Branch; MOORE, SOPHIE - London School Of Hygiene & Tropical Medicine; FULFORD, ANTHONY - London School Of Hygiene & Tropical Medicine; PRENTICE, ANDREW - London School Of Hygiene & Tropical Medicine; WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)

Submitted to: Genome Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2015
Publication Date: 6/11/2015
Citation: Silver, M.J., Kessler, N.J., Hennig, B.J., Dominguez-Salas, P., Laritsky, E., Baker, M.S., Coarfa, C., Hernandez-Vargas, H., Castelino, J.M., Routledge, M.N., Gong, Y., Herceg, Z., Lee, Y., Lee, K., Moore, S.E., Fulford, A.J., Prentice, A.M., Waterland, R.A. 2015. Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment. Genome Biology. doi:10.1186/S13059-015-0660-Y.

Interpretive Summary: Our laboratory has for many years studied metastable epialleles in mice. These are genomic regions attracted attention because they cause visible differences in various characteristics among mice that are genetically identical. For example, the mouse agouti viable yellow metastable epiallele affects the regulation of a gene that determines both fur color and body weight regulation. Extensive research showed that this interindividual variation was due to random individual differences, not in the DNA sequence, but in how the DNA is marked (and read) in each individual – so called epigenetic information. Recently, we have been identifying metastable epialleles in humans. This paper describes our latest genome-wide screen for such regions, and our discovery that a known tumor suppressor gene, VTRNA2-1, is a human metastable epiallele. This has important implications for cancer, in that one's epigenetic state at VTRNA2-1 (which is influenced by maternal nutrition around the time of conception) may predict risk of cancer.

Technical Abstract: 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. 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. 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.