Transcriptome Changes Affecting Hedgehog and Cytokine Signalling in the Umbilical Cord: Implications for Disease Risk

Abstract

BackgroundBabies born at lower gestational ages or smaller birthweights have a greater risk of poorer health in later life. Both the causes of these sub-optimal birth outcomes and the mechanism by which the effects are transmitted over decades are the subject of extensive study. We investigated whether a transcriptomic signature of either birthweight or gestational age could be detected in umbilical cord RNA.MethodsThe gene expression patterns of 32 umbilical cords from Singaporean babies of Chinese ethnicity across a range of birthweights (1698–4151 g) and gestational ages (35–41 weeks) were determined. We confirmed the differential expression pattern by gestational age for 12 genes in a series of 127 umbilical cords of Chinese, Malay and Indian ethnicity.ResultsWe found that the transcriptome is substantially influenced by gestational age; but less so by birthweight. We show that some of the expression changes dependent on gestational age are enriched in signal transduction pathways, such as Hedgehog and in genes with roles in cytokine signalling and angiogenesis. We show that some of the gene expression changes we report are reflected in the epigenome.ConclusionsWe studied the umbilical cord which is peripheral to disease susceptible tissues. The results suggest that soma-wide transcriptome changes, preserved at the epigenetic level, may be a mechanism whereby birth outcomes are linked to the risk of adult metabolic and arthritic disease and suggest that greater attention be given to the association between premature birth and later disease risk.

Fetal DNA Methylation Associates with Early Spontaneous Preterm Birth and Gestational Age

“…Recent studies in the field support associations between GA and both DNA methylation and gene expression differences, but note lesser or no associations with birth weight [18], [48]. Similarly, in this study we identified numerous associations between DNA methylation and PTB, which is measured by GA, but no associations with percentile birth weight.…”

“…Similarly, in this study we identified numerous associations between DNA methylation and PTB, which is measured by GA, but no associations with percentile birth weight. Based on this, Stunkel and colleagues hypothesize that birth weight may be a less appropriate measure of adverse outcomes than GA [48]. Along these lines, we identified associations between GA and DNA methylation of CpG sites in insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), a developmentally regulated gene that binds IGF2 and has been a focus of the fetal programming literature [49].…”

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

“…Thus the environmental epigenetic hypothesis (Seckl and Meaney 1993;Meaney and Ferguson-Smith 2010) suggests that the in utero environment affects the epigenome and that resulting epigenetic marks alter physiology to affect later disease risk ). Evidence for this hypothesis derives from studies documenting the relationship between specific DNA methylation marks, in utero environments, and later phenotypes (Guo et al 2008;Perera et al 2009;Pilsner et al 2009Pilsner et al , 2012van der Kaay et al 2009;Feinberg et al 2010;Kaminen-Ahola et al 2010;Ollikainen et al 2010;Fryer et al 2011;Hoyo et al 2011;Tobi et al 2011;Relton et al 2012;Stunkel et al 2012). For example, maternal carbohydrate intake in early pregnancy and offspring adiposity at 9 yr of age associate with the DNA methylation level of the RXRA promoter in the umbilical cord (Godfrey et al 2011).…”

Insights from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) Cohort Study

“…However, birth weight, even at extremes, was not an important driver. Transcriptome changes were found to relate to DNA methylation levels, with possible implications for the risk of NCD later in life [6]. …”

“…Maternal influences can affect the development of the offspring through mechanisms of developmental plasticity, involving epigenetic modifications that regulate chromatin structure and gene transcription [4,5,6]. The sustained influence of the early environment on health over the course of the lifespan forms the basis of the ‘developmental origins of health and disease (DOHaD)' paradigm [4].…”