Descrizione del progetto
Il ruolo dei trasposoni nello sviluppo della placenta
Lo sviluppo della placenta dipende in gran parte dalla genetica del feto e della madre. Comprendere i meccanismi sottostanti a tale sviluppo fornirebbe conoscenze importanti sulle complicazioni della gravidanza, come la preeclampsia e la limitazione della crescita fetale. Il progetto InvADeRS, finanziato dall’UE, sta approfondendo il ruolo degli elementi trasponibili (ET), ovvero quegli elementi mobili del DNA presenti nel genoma dei mammiferi emersi durante l’evoluzione a causa di infezioni virali. I ricercatori desiderano comprendere se gli ET regolano l’espressione genica nella placenta degli esseri umani, causando l’invasione della placenta nell’utero materno. Identificare i trasposoni specifici con potenziale regolatorio indica i percorsi chiave coinvolti in una gravidanza regolare e potrebbe promuovere ulteriori ricerche in questo campo.
Obiettivo
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.
Campo scientifico
- natural sciencesbiological scienceszoologymammalogyprimatology
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesclinical medicineobstetricsfetal medicine
- natural sciencesbiological sciencesgeneticsgenomes
- medical and health sciencesbasic medicinephysiologyhomeostasis
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-RI - RI – Reintegration panelCoordinatore
E1 4NS London
Regno Unito