Abstract
The DOHaD (developmental origins of health and disease) hypothesis claims that fetal malnutrition or exposure to environmental pollutants may affect their lifelong health. Epigenetic changes may play significant roles in DOHaD; however, access to human fetuses for research has ethical and technical hurdles. Umbilical cord blood (CB) has been commonly used as an epigenetic surrogate of fetuses, but it does not provide direct evidence of fetal exposure to pollutants. Here, we propose umbilical cord tissue (UC), which accumulates substances delivered to fetuses during gestation, as an alternative surrogate for epigenetic studies on fetuses. To explore the feasibility to examine UC epigenome by deep sequencing, we determined CpG methylation profiles of human postnatal UC by reduced representation bisulfite sequencing. Principal component analysis clearly separated the DNA methylomes of UC and CB pairs isolated from the same newborn (n = 10). Although all UC chromosomes were modestly hypomethylated compared to CB chromosomes, GO analysis revealed strong enrichment of differentially methylated regions (DMRs) at promoter-associated CpG islands in the HOX gene clusters and other genes encoding transcription factors involved in determination of the body pattern. DNA methylomes of UC autosomes were largely comparable between males and females. Deficiency of folate during pregnancy has been suggested to affect fetal DNA methylation to cause congenital anomalies. Whereas DNA methylome of UC was not significantly affected by early-gestational (12 weeks) low levels of maternal plasma folate (< 8 ng/ml, n = 10) compared to controls (>19 ng/mL, n = 10), two specific loci of LTR12C endogenous retroviruses in chromosome 12 were significantly hypermethylated in the low-folate group. Our study suggests that UC is useful as an alternative surrogate for studying environmental effects on DNA methylation in human fetuses, compensating CB by providing additional information about epigenetic regulation of genes involved in developmental body patterning and endogenous retroviruses.
Highlights
Developmental Origins of Health and Disease (DOHaD) is a hypothesis claiming that the early life environment, including fetal to infantile stages of human development, can impact the risk of chronic diseases from childhood to adulthood
These results indicate that representation bisulfite sequencing (RRBS) analysis of CpG methylation can be performed for the genomic DNA isolated from human umbilical cord tissue (UC) specimens with quality control parameters comparable to those of human cord blood (CB) specimens
X-Y plotting of CpG methylation in UC and CB genomes revealed a high-density region of dots reflecting very strong methylation in both UC and CB (Fig 1B, region a). Another high-density region (b) indicated a large number of strongly demethylated CpG sites in both UC and CB. The presence of these strongly methylated or demethylated CpG sites shared by UC and CB agreed with the dichotomy pattern of CpG methylation shown in S1C Fig. The third high-density region (c) aligned along the diagonal line connecting the regions a and b showed a discernible bias towards the bottom, resulting in the crescent shape of this region
Summary
Developmental Origins of Health and Disease (DOHaD) is a hypothesis claiming that the early life environment, including fetal to infantile stages of human development, can impact the risk of chronic diseases from childhood to adulthood. Despite the importance of DNA methylome profiling of human fetuses and newborn children, access to their tissue specimens is limited due to ethical restrictions and technical risk of affecting normal development For this reason, non-invasive surrogate tissues of human neonates–namely, placenta, umbilical cord blood (CB), and umbilical cord tissue (UC)–have been playing important roles in estimating epigenetic impact of prenatal stresses. Godfrey et al have shown that augmented DNA methylation in UC at the retinoid X receptorα (RXRA) gene promoter was associated with an increase in sex-adjusted childhood fat mass at 6 or 9 years of age as well as a greater amount of maternal carbohydrate intake during early pregnancy [19] These studies support the potential usefulness of UC, without separation of its heterogeneous structures, for epigenetic studies in the context of DOHaD
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