Abstract
BackgroundDNA methylation has recently been identified as a mediator between in utero famine exposure and a range of metabolic and psychiatric traits. However, genome-wide analyses are scarce and cross-sectional analyses are hampered by many potential confounding factors. Moreover, causal relations are hard to identify due to the lack of controlled experimental designs. In the current study, we therefore combined a comprehensive assessment of genome-wide DNA methylation differences in people exposed to the great Chinese famine in utero with an in vitro study in which we deprived fibroblasts of nutrition.MethodsWe compared whole blood DNA methylation differences between 25 individuals in utero exposed to famine and 54 healthy control individuals using the HumanMethylation450 platform. In vitro, we analyzed DNA methylation changes in 10 fibroblast cultures that were nutritionally deprived for 72 h by withholding fetal bovine serum.ResultsWe identified three differentially methylated regions (DMRs) in four genes (ENO2, ZNF226, CCDC51, and TMA7) that were related to famine exposure in both analyses. Pathway analysis with data from both Chinese famine samples and fibroblasts highlighted the nervous system and neurogenesis pathways as the most affected by nutritional deprivation.ConclusionsThe combination of cross-sectional and experimental data provides indications that biological adaptation to famine leads to DNA methylation changes in genes involved in the central nervous system.
Highlights
Deoxyribonucleic acid (DNA) methylation has recently been identified as a mediator between in utero famine exposure and a range of metabolic and psychiatric traits
The three replicated differentially methylated regions (DMRs) are all hypomethylated in relation to famine exposure and highlight four gene promoters: DMR1, enolase 2 (ENO2), and DMR2, zinc finger protein 226 (ZNF226)
The study from Hannon et al [29] was used as a lookup for the relation between methylation in blood and brain for the identified loci. cg08003732 and cg13334990 loci in ENO2 gene were all significantly correlated between blood and four brain regions: the prefrontal cortex (PFC), entorhinal cortex (EC), superior temporal gyrus (STG), and cerebellum (CER)
Summary
DNA methylation has recently been identified as a mediator between in utero famine exposure and a range of metabolic and psychiatric traits. We combined a comprehensive assessment of genome-wide DNA methylation differences in people exposed to the great Chinese famine in utero with an in vitro study in which we deprived fibroblasts of nutrition. This study identified persistent differential methylation of the insulin-like growth factor II (IGF2), as a key human growth and development factor involved in the response to famine in utero [3]. Subsequent studies of this cohort identified DNA methylation changes as mediators of the association between maternal famine and metabolic disease in adulthood [6, 8]. Other epigenetic differences associated with famine exposure in utero have been related to schizophrenia [9] and type 2 diabetes [10]
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