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

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    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.

    Original languageEnglish (US)
    Article number118
    JournalGenome Biology
    Volume16
    Issue number1
    DOIs
    StatePublished - Jun 11 2015

    Fingerprint

    Epigenomics
    epigenetics
    tumor
    methylation
    DNA methylation
    DNA Methylation
    human diseases
    DNA
    neoplasms
    genomics
    lymphocytes
    blood
    Lymphocytes
    Gambia
    bisulfites
    Neoplasms
    Gastrulation
    imprinting
    hair follicles
    DNA Transposable Elements

    ASJC Scopus subject areas

    • Cell Biology
    • Ecology, Evolution, Behavior and Systematics
    • Genetics

    Cite this

    Silver, M. J., Kessler, N. J., Hennig, B. J., Dominguez-Salas, P., Laritsky, E., Baker, M. S., ... Waterland, R. A. (2015). Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment. Genome Biology, 16(1), [118]. https://doi.org/10.1186/s13059-015-0660-y

    Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment. / Silver, Matt J.; Kessler, Noah J.; Hennig, Branwen J.; Dominguez-Salas, Paula; Laritsky, Eleonora; Baker, Maria S.; Coarfa, Cristian; Hernandez-Vargas, Hector; Castelino, Jovita M.; Routledge, Michael N.; Gong, Yun Yun; Herceg, Zdenko; Lee, Yong Sun; Lee, Kwanbok; Moore, Sophie E.; Fulford, Anthony J.; Prentice, Andrew M.; Waterland, Robert A.

    In: Genome Biology, Vol. 16, No. 1, 118, 11.06.2015.

    Research output: Contribution to journalArticle

    Silver, MJ, Kessler, NJ, Hennig, BJ, Dominguez-Salas, P, Laritsky, E, Baker, MS, Coarfa, C, Hernandez-Vargas, H, Castelino, JM, Routledge, MN, Gong, YY, Herceg, Z, Lee, YS, Lee, K, Moore, SE, Fulford, AJ, Prentice, AM & Waterland, RA 2015, 'Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment', Genome Biology, vol. 16, no. 1, 118. https://doi.org/10.1186/s13059-015-0660-y
    Silver, Matt J. ; Kessler, Noah J. ; Hennig, Branwen J. ; Dominguez-Salas, Paula ; Laritsky, Eleonora ; Baker, Maria S. ; Coarfa, Cristian ; Hernandez-Vargas, Hector ; Castelino, Jovita M. ; Routledge, Michael N. ; Gong, Yun Yun ; Herceg, Zdenko ; Lee, Yong Sun ; Lee, Kwanbok ; Moore, Sophie E. ; Fulford, Anthony J. ; Prentice, Andrew M. ; Waterland, Robert A. / Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment. In: Genome Biology. 2015 ; Vol. 16, No. 1.
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    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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    T1 - Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment

    AU - Silver, Matt J.

    AU - Kessler, Noah J.

    AU - Hennig, Branwen J.

    AU - Dominguez-Salas, Paula

    AU - Laritsky, Eleonora

    AU - Baker, Maria S.

    AU - Coarfa, Cristian

    AU - Hernandez-Vargas, Hector

    AU - Castelino, Jovita M.

    AU - Routledge, Michael N.

    AU - Gong, Yun Yun

    AU - Herceg, Zdenko

    AU - Lee, Yong Sun

    AU - Lee, Kwanbok

    AU - Moore, Sophie E.

    AU - Fulford, Anthony J.

    AU - Prentice, Andrew M.

    AU - Waterland, Robert A.

    PY - 2015/6/11

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    N2 - 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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