A Genome Scale Transcriptional Regulatory Model of the Human Placenta

Abstract

Gene regulation is essential to placental function and fetal development. We report a genome-scale transcriptional regulatory network (TRN) of the human placenta built using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out of sample R2 value greater than 0.25 for 74% of target genes. We performed siRNA knockdowns of 4 TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for 3 of the 4 TFs. Our final model contained 113,158 interactions across 391 TFs and 7,712 target genes and is publicly available. We identified six TFs which were significantly enriched as regulators for genes previously associated with preterm birth.

Associations Between Prenatal Vitamin D and Placental Gene Expression

“…In this analysis, ARNT2 , BHLHE40 , FOSL2 , and NFKB1 were positively associated with vitamin D levels and their targets were enriched in the darkgreen WGCNA module. In a placental-specific transcription regulatory network, BHLHE40 , FOSL2 , and NFKB1 regulate each other (47). Additionally, ARNT2 is regulated by VDR and regulates VDR and BHLHE40 (47).…”

“…In a placental-specific transcription regulatory network, BHLHE40 , FOSL2 , and NFKB1 regulate each other (47). Additionally, ARNT2 is regulated by VDR and regulates VDR and BHLHE40 (47). ARNT2 and its paralog ARNT dimerize with HIF1A to regulate the hypoxic response and dimerize with AHR to regulate placental vascular development through pregnancy (68,71).…”

“…Modules were characterized by identifying hub genes, conducting KEGG pathway over- representation analysis ( limma::kegga function) on gene members, and TF over-representation analysis using a placenta-specific transcription regulatory network (47). Genes assigned to a given module that were highly correlated with that module’s eigengene (| r |>0.8) were selected as the given module’s hubgenes.…”