Epigenetics, Nutrition and Growth

Berthold Koletzko


The fascinating research field on epigenetic, biochemical modifications of the human genome in relation to nutrition and growth continues to expand. A search in the US National Library of Medicine performed on January 1, 2021 with the search term “epigenetic* AND (nutrition OR growth)” revealed 2,418 entries for 2017, 2,521 for 2018, 2,623 for 2019, and 2,259 for the then still incomplete database for 2020. Therefore, this chapter cannot provide a comprehensive overview, but the author subjectively selected some publications that appeared in 2019 and 2020 which he considered noteworthy.

Most but not all studies measured DNA methylation at 15 cytosine-(phosphate)-guanine sites (CpGs), given that convenient albeit somewhat expensive commercial chip technology for genome-wide profiling of human DNA methylation is available. A major challenge is the complex bioinformatic analysis of the evolving large datasets arising mostly from observational cohort studies that report associations. Therefore, replication of findings in independent studies is most valuable. Studies published during the time period that was reviewed support the concept of an important impact of epigenetic programming through environmental exposures during early life for lasting health outcomes. This is underpinned by reported associations of differentially methylated CpG regions to immediate predictors of long-term health such as birth weight and duration of gestation, and to later health outcomes such as asthma, the most common chronic disease in children. Reported predictors of differentially methylated CpG regions comprise infant sex, maternal BMI at conception, gestational weight gain, and maternal hypertension, all of which are well known to correlate with immediate and later health outcomes. Maternal environment, lifestyle, and diet appear to matter, indicated by a lasting association of pre-pregnancy socioeconomic status with epigenetic marks at birth and up to early school age, and by repeatedly reported associations with the quality of maternal dietary fatty acid intakes. It is tempting to speculate that epigenetic DNA methylation could be one of the missing mechanistic links by which maternal and fetal biological characteristics and environmental cues predict the child’s later health outcomes. Fathers appear to matter, too, given that the fathers’ BMI at conception was associated both with infant birth weight and epigenome-wide DNA methylation patterns in their children at birth and up to 7 years of age. At later ages, the time of pubertal onset was related to DNA methylation, suggesting that epigenetic imprinting in early life may influence the biological processes and health consequences of later puberty development. The results available at this time are truly exciting. Better understanding of the biological mechanisms by which lifestyle and environment during developmental plasticity during early life may modulate long-term health and development could offer new opportunities for even more effective strategies to promote the health of populations and of individuals at increased risk.

Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Comments: This is a collaborative analysis of the PACE consortium that performs joint analyses of epigenetic measurements from numerous studies in pregnant women and children. Here, DNA methylation in about 3,500 neonates and in about 3,000 children predicted asthma, the most common chronic disease in children. Numerous associations between childhood asthma and numerous novel differentially methylated CpGs and regions were identified in relation to this common health outcome. Six of the significant CpGs were in DNAse hypersensitivity sites, consistent with a potential regulatory effect on gene function. Most results obtained in blood cells could be replicated in studies of nasal respiratory epithelium or eosinophils. The results underline the potential high relevance of epigenetic DNA methylation for modulating important health endpoints.


DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases

Comments: In a sample of about 300 women from a prospective fetal growth study, the authors found a significant association of birth weight with differential methylation at 15 CpG sites (CpGs) in placental tissue. In one-third of the birth weight associated CpG sites, DNA methylation was associated with expression of proximal genes in placenta. In five out of the 15 identified CpGs, methylation in adult blood had been previously associated with adult chronic diseases, consistent with the hypothesis that placental DNA methylation modulating birth weight regulation may also predict offspring risk of later life chronic diseases.


Being born large for gestational age is associated with increased global placental DNA methylation

Comments: This study assessed global DNA methylation in a large study with more than 1,000 placental samples and found significantly higher DNA methylation in infants born large compared to those born with appropriate weight for gestational age. These results should prompt further investigation of potential underlying mechanisms.


Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Comments: This collaboration of the PACE consortium evaluated genome-wide DNA methylation data from cord blood cells in a very large sample of 3,648 neonates born after pregnancies without common complications, induced delivery or caesarean section. Gestational age at birth was significantly associated with 4,966 CpG sites. Results were generally consistent when analyses were restricted to term births. The authors found various functional elements enriched among gestational age-associated CpGs. CpG island shores, enhancers, and DNase I hypersensitive sites were particularly susceptible to DNA methylation changes in relation to gestational age, which points to a likely functional importance of these sites. The results suggest epigenomic plasticity of fetal development in relation to duration of gestation, which may also be relevant to preterm birth.


Sex-specific epigenetic gene activation profiles are differentially modulated in human placentas affected by intrauterine growth restriction

Comments: The protein histone H3 serves to facilitate DNA packaging in human and other eukaryotic cells. Modifications of H3 alter gene accessibility for transcription. H3K4me3 is an epigenetically modified H3 with three methyl groups linked to the fourth lysine residue of H3 that generally activates the transcription of nearby genes. H3K9ac is a modified H3 with acetylation at the 9th lysine residue, generally activating the transcription of nearby genes. Meister et al. found a significantly lower expression of the histone protein H3K4me in the syncytiotrophoblast in female but not male IUGR placentas. In contrast, H3K9ac expression was downregulated in the decidua of male IUGR fetuses. These data indicate possible sex-specific differences in placental epigenetic mechanisms and effects.


Placental DNA methylation changes associated with maternal pre-pregnancy BMI and gestational weight gain

Comments: This study explored genome-wide placental DNA methylation in about 300 women in a prospective fetal growth study, and gene expression was determined in samples from 75 women. A number of differentially methylated CpG sites were identified that were significantly associated with pre-pregnancy BMI and with gestational weight gain. Some of these sites were previously implicated in obesity traits in children and adults. Thus, it appears possible that placental epigenetic changes induced by high maternal BMI and gestational weight gain could explain intrauterine mechanisms in the developmental origins of obesity in the offspring.


Differential DNA methylation in placenta associated with maternal blood pressure during pregnancy

Comments: The same group that published the preceding study analyzed placental DNA methylation data in the same sample in relation to maternal blood pressure and reports methylation at 24 CpG sites associated with trimester-specific maternal SBP and DBP. These results point to potential mechanisms underpinning the associations between increased maternal blood pressure, fetal development, and adult diseases.


Association of periconception paternal body mass index with persistent changes in DNA methylation of offspring in childhood

Comments: Fathers matter, too, according to this study. In this prospective cohort study, the fathers’ BMI at conception was associated with infant birth weight and as well as epigenome-wide DNA methylation patterns in their children at birth and at the ages of 3 and 7 years. Thus, results are compatible with the hypothesis that the well-documented association between fathers’ BMI and children’s risk of overweight is not only due to shared environments and behaviors but also to epigenetic programming, which would have important consequences for transgenerational prevention strategies.


Socioeconomic status and DNA methylation from birth through mid-childhood: A prospective study in Project Viva

Comments: This prospective cohort study in a large sample of more than 600 mother-child dyads found prenatal socioeconomic status significantly associated with several differentially methylated CpG sites at birth and persisting at pre-school and early school age. These results point to a possible effect of lifestyle conditions linked to socioeconomic status on epigenetic programming of later health and disease. The specific prenatal environmental or dietary factors of influence need to be identified to develop preventive intervention strategies.


Associations between maternal body mass index and diet composition with placental DNA methylation at term

Comments: Genome-wide DNA methylation was assessed in placental tissue from normal weight mothers (n = 72) and overweight/obese mothers (n = 78). The authors found a significant association of 185 differentially methylated placental CpGs with maternal BMI assessed before week 10 of gestation. Analysis of maternal dietary intake assessed with 3-day food records at each trimester showed an association of maternal saturated fat consumption with methylation of 302 CpGs, with affected genes related to chromatin, IGF receptor, PI3K, and NOS signaling. The results suggest that both maternal diet and body mass may induce epigenetic changes in placental genes and placental functions.


Maternal fatty acid concentrations and newborn DNA methylation

Comments: The authors measured plasma fatty concentrations in more than 300 women prior to conception and during the first trimester of pregnancy and associated this biomarker of both dietary intake and endogenous metabolism with DNA methylation in cord blood. Preconception maternal plasma fatty acid concentration was associated with offspring DNA methylation, in particular the long-chain n3 polyunsaturated fatty acids (PUFA) EPA and DHA, n-6 PUFA, monounsaturated, saturated, and trans-fatty acids. In contrast, maternal fatty acid values in the first trimester were largely unrelated to DHA methylation. These results point to a potential window of preventive opportunity through improving diet during the pre-conception period.


Age at onset of different pubertal signs in boys and girls and differential DNA methylation at age 10 and 18 years: An epigenome-wide follow-up study

Comments: In 244 girls and 226 boys, age at pubertal onset was related to genome-wide analysis of CpG methylation. After occurrence of indicators of puberty, methylation of 63,019 CpGs changed statistically significantly in girls and 3,072 in boys. Most of the affected genes are known to be related to biological processes of puberty. The results are compatible with the hypothesis that gene methylation and related changes in gene expression are involved with the biological processes of puberty and potential developmental and health consequences.