Abstract
BackgroundThe placenta is the principal organ regulating intrauterine growth and development, performing critical functions on behalf of the developing fetus. The delineation of functional networks and pathways driving placental processes has the potential to provide key insight into intrauterine perturbations that result in adverse birth as well as later life health outcomes.ResultsWe generated the transcriptome-wide profile of 200 term human placenta using the Illumina HiSeq 2500 platform and characterized the functional placental gene network using weighted gene coexpression network analysis (WGCNA). We identified 17 placental coexpression network modules that were dominated by functional processes including growth, organ development, gas exchange and immune response. Five network modules, enriched for processes including cellular respiration, amino acid transport, hormone signaling, histone modifications and gene expression, were associated with birth weight; hub genes of all five modules (CREB3, DDX3X, DNAJC14, GRHL1 and C21orf91) were significantly associated with fetal growth restriction, and one hub gene (CREB3) was additionally associated with fetal overgrowth.ConclusionsIn this largest RNA-Seq based transcriptome-wide profiling study of human term placenta conducted to date, we delineated a placental gene network with functional relevance to fetal growth using a network-based approach with superior scale reduction capacity. Our study findings not only implicate potential molecular mechanisms underlying fetal growth but also provide a reference placenta gene network to inform future studies investigating placental dysfunction as a route to future disease endpoints.
Highlights
The placenta is the principal organ regulating intrauterine growth and development, performing critical functions on behalf of the developing fetus
Placental gene network modules associated with birth weight To demonstrate the functional relevance of the placenta network identified above, we further evaluated modulebased differences in fetal-growth related gene pathways
The generated profile stems from non-pathological, term placenta, providing a characterization of the baseline placental transcriptional landscape and the role that normal variation might play in defining patterns of intrauterine development in the general population
Summary
The placenta is the principal organ regulating intrauterine growth and development, performing critical functions on behalf of the developing fetus. Systems biology methods that apply a networks-based analysis of transcriptome-wide data better capture the complexity of inter-gene relationships and the pathways they participate in to give rise to disease processes, and, hold the opportunity to better define the co-regulatory patterns that underlie complex phenotypes. Methods such as weighted gene co-expression network analysis (WGCNA) have been successfully applied in a number of tissues in relation to various health outcomes [12,13,14,15]. The utility of this approach was demonstrated in a recently published study focusing on highly variable genes (n ~ 3000) in a set of 16 placenta that showcased both conservation and divergence between human and mouse placental networks [18]
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