Editors' ChoiceEpigenetics

Timing is everything

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Science Translational Medicine  10 Jun 2015:
Vol. 7, Issue 291, pp. 291ec99
DOI: 10.1126/scitranslmed.aac5099

Studies of the Dutch Hunger Winter of 1944 to 1945—a 6-month famine—suggest that extreme calorie restriction during pregnancy increases the risk of adult-onset diseases via epigenetic alterations that occur during the early gestation period. Indeed, the quality of the maternal nutrient environment during pregnancy is strongly associated with a variety of adult-onset metabolic diseases such as obesity, diabetes, and dyslipidemia. However, it has been unclear whether selected time periods are particularly sensitive to prenatal nutrient perturbations. Now, to identify a critical window of exposure for epigenetic changes, Tobi et al. performed an epigenome-wide association study of individuals who were exposed, in utero, to the Dutch famine and compared the results with siblings and other control subjects who did not experience famine during fetal development.

The authors classified subjects into four famine-exposure periods based on the date of the mother’s last menstrual period and gestation weeks 1 to 10, 11 to 20, 21 to 30, or 31 to delivery. DNA methylation was assessed (with the Illumina 450k array) in whole-blood samples from 422 individuals with prenatal famine exposure and 463 controls without prenatal famine exposure. After careful statistical analyses, the authors found that weeks 1 to 10 corresponded to the critical prenatal-famine-exposure time period for adult DNA methylation changes—the time during which the hematopoietic system is formed. Furthermore, famine exposure during weeks 1 to 10 was associated with the DNA methylation status of four CpG dinucleotides in genes related to growth, differentiation, and metabolism. The authors hypothesized that the observed timing-specific associations suggest an intrinsic sensitivity of newly developing tissues. Similar analysis of other tissue types will shed further light on this question.

Maternal nutrient exposure also might alter the cell subtype composition of the tissue that is developing during the exposure period. Single-cell methylation assays or epigenetic heterogeneity analysis using single nucleotide–resolution DNA methylation assays might be necessary to decipher the mechanisms that underlie the epigenetic origins of metabolic diseases.

E. W. Tobi et al., Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome. Intl. J. Epidemiol. 10.1093/ije/dyv043 (2015). [Full Text]

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