Genome-wide maps of distal gene regulatory enhancers active in the human placenta.

Placental dysfunction is implicated in many pregnancy complications, including preeclampsia and preterm birth (PTB). While both these syndromes are influenced by environmental risk factors, they also have a substantial genetic component that is not well understood. Precisely controlled gene expression during development is crucial to proper placental function and often mediated through gene regulatory enhancers. However, we lack accurate maps of placental enhancer activity due to the challenges of assaying the placenta and the difficulty of comprehensively identifying enhancers. To address the gap in our knowledge of gene regulatory elements in the placenta, we used a two-step machine learning pipeline to synthesize existing functional genomics studies, transcription factor (TF) binding patterns, and evolutionary information to predict placental enhancers. The trained classifiers accurately distinguish enhancers from the genomic background and placental enhancers from enhancers active in other tissues. Genomic features collected from tissues and cell lines involved in pregnancy are the most predictive of placental regulatory activity. Applying the classifiers genome-wide enabled us to create a map of 33,010 predicted placental enhancers, including 4,562 high-confidence enhancer predictions. The genome-wide placental enhancers are significantly enriched nearby genes associated with placental development and birth disorders and for SNPs associated with gestational age. These genome-wide predicted placental enhancers provide candidate regions for further testing in vitro, will assist in guiding future studies of genetic associations with pregnancy phenotypes, and aid interpretation of potential mechanisms of action for variants found through genetic studies.