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2015 ; 16
(1
): 118
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gab.com Text
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Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human
epiallele responsive to periconceptional environment
#MMPMID26062908
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
Genome Biol
2015[Jun]; 16
(1
): 118
PMID26062908
show ga
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.