Investigating the activity of transposon derived regulatory sequences in the placenta
Aberrant epigenetic regulation of placental function is implicated in several complications of pregnancy, such as preeclampsia, recurrent pregnancy loss and fetal growth restriction. Notably, the placenta has a unique epigenetic landscape, permissive for the activity of transposable element (TE) derived DNA sequences. TEs are often co-opted by the host genome as cis-regulatory elements, driving tissue- and species-specific gene expression programs. Indeed, TEs contribute many placental-specific enhancers in mouse trophoblast. However, the presence and role of a similar TE-derived regulatory network has not been explored in human trophoblast. As TEs are highly species-specific, such a network in humans would be expected to regulate species-specific placental characteristics, such as the deep interstitial invasion unique to great apes. TE-derived regulatory elements may therefore be important for placental homeostasis and be involved in diseases characterised by aberrant placental invasion. I propose to map TE-derived cis-regulatory sequences in human trophoblast ex vivo using their histone modification signatures. I will assess the regulatory potential of candidate TEs through transcriptomic analyses and motif analysis to reveal transcription factor binding sites, highlighting promising candidates of importance in the human placenta. I will then directly test the function of top TE candidates using CRISPR-Cas9 genome editing of the TEs in trophoblast in vitro, and measuring changes in expression of target genes. Finally, I will elucidate epigenetic and coding differences between complicated and normal control placentas at the functional regulatory TE loci I find, to identify correlations with disease. This project will provide a comprehensive analysis of an as-yet unexplored aspect of human placental epigenetic regulation, and potentially identify novel causes of common unexplained complications of human pregnancy.