Transcriptome changes affecting Hedgehog and cytokine signalling in the umbilical cord: implications for disease risk.

Walter Stünkel,Seang Mei Saw,Joanna D Holbrook,Li Chen,Emilia Tng,Allan M Sheppard,Roy Joseph,Yung Seng Lee,Jun Hao Tan,Mei-Lyn Ong,Clara Y Cheong,Yap-Seng Chong,Siew Boom Chew,Hong Pan,Michael J Meaney,Kenneth Kwek,Peter D Gluckman,Cees Oudejans

doi:10.1371/journal.pone.0039744

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.

Highlights

Birth outcomes defined by gestational age and birth weight have far reaching consequences across the life-course
[14,15,16,17,18,19,20,21] in the umbilical cord associated with extreme intrauterine experience or birth outcomes, of particular interest to us and relevant to global health concerns are the molecular mechanisms of inter-individual variability operating within the normal range [22], as long-term effects of the prenatal state can be readily demonstrated within children of normal birthweight and gestation [9,23,24]
We suggest that lower birth weight and earlier gestational ages, leaves an epigenetic echo that affects the risk for diseases such as type 2 diabetes mellitus and osteoarthritis in later life

Summary

Introduction

Birth outcomes defined by gestational age and birth weight have far reaching consequences across the life-course. While several groups have found transcriptomic [12,13] and epigenetic marks [14,15,16,17,18,19,20,21] in the umbilical cord associated with extreme intrauterine experience or birth outcomes, of particular interest to us and relevant to global health concerns are the molecular mechanisms of inter-individual variability operating within the normal range [22], as long-term effects of the prenatal state can be readily demonstrated within children of normal birthweight and gestation [9,23,24]. Babies 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.

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Results

Discussion

Conclusion