Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles.
Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles.
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DOI：
10.1371/journal.pgen.1001252
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发表时间：
2010-12-23
期刊：
影响因子：
4.5
通讯作者：
Prentice AM
中科院分区：
文献类型：
--
作者：
Waterland RA;Kellermayer R;Laritsky E;Rayco-Solon P;Harris RA;Travisano M;Zhang W;Torskaya MS;Zhang J;Shen L;Manary MJ;Prentice AM
Throughout most of the mammalian genome, genetically regulated developmental programming establishes diverse yet predictable epigenetic states across differentiated cells and tissues. At metastable epialleles (MEs), conversely, epigenotype is established stochastically in the early embryo then maintained in differentiated lineages, resulting in dramatic and systemic interindividual variation in epigenetic regulation. In the mouse, maternal nutrition affects this process, with permanent phenotypic consequences for the offspring. MEs have not previously been identified in humans. Here, using an innovative 2-tissue parallel epigenomic screen, we identified putative MEs in the human genome. In autopsy samples, we showed that DNA methylation at these loci is highly correlated across tissues representing all 3 embryonic germ layer lineages. Monozygotic twin pairs exhibited substantial discordance in DNA methylation at these loci, suggesting that their epigenetic state is established stochastically. We then tested for persistent epigenetic effects of periconceptional nutrition in rural Gambians, who experience dramatic seasonal fluctuations in nutritional status. DNA methylation at MEs was elevated in individuals conceived during the nutritionally challenged rainy season, providing the first evidence of a permanent, systemic effect of periconceptional environment on human epigenotype. At MEs, epigenetic regulation in internal organs and tissues varies among individuals and can be deduced from peripheral blood DNA. MEs should therefore facilitate an improved understanding of the role of interindividual epigenetic variation in human disease. There is growing interest in the possibility that interindividual epigenetic variation plays an important role in a broad range of human diseases. The tissue-specificity of epigenetic regulation, however, will in many cases make it difficult to obtain the appropriate tissues in which to perform large-scale studies linking epigenetic dysregulation to disease. We have used an innovative two-tissue DNA methylation screen to identify genomic regions that exhibit interindividual epigenetic variation which occurs systemically—i.e. similarly in all tissues. Such regions—called metastable epialleles—have previously been identified in mice because they cause visible phenotypic variation amongst genetically identical individuals. Indeed, we found that even monozygotic twins show substantial epigenetic discordance at these loci. Further, we show that, as in mice, establishment of DNA methylation at these putative human metastable epialleles is labile to maternal environment around the time of conception. Metastable epialleles should facilitate an improved understanding both of the role of interindividual epigenetic variation in human disease and of the effects of early environment on the establishment of human epigenotype.
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影响因子：
30.8
作者：
Kerkel, Kristi;Spadola, Alexandra;Tycko, Benjamin
通讯作者：
Tycko, Benjamin
影响因子：
5.2
作者：
Pembrey, ME;Bygren, LO;Golding, J
通讯作者：
Golding, J
DOI：
10.1073/pnas.0500398102
发表时间：
2005-07-26
影响因子：
11.1
作者：
Fraga, MF;Ballestar, E;Esteller, M
通讯作者：
Esteller, M
DOI：
10.1073/pnas.0906183107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Feinberg, Andrew P.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.
DOI：
10.1073/pnas.0703739104
发表时间：
2007-08-07
影响因子：
11.1
作者：
Dolinoy, Dana C.;Huang, Dale;Jirtle, Randy L.
通讯作者：
Jirtle, Randy L.