Descrizione del progetto
Approfondire i percorsi genetici della determinazione del sesso
In numerose specie di mammiferi il sesso viene determinato a livello genetico mediante l’espressione di uno o diversi geni trasportati dai cromosomi sessuali. Sebbene esista un antagonismo tra i percorsi maschili e femminili nel rinforzo del destino, il meccanismo di interazione e gli eventi a valle sono tuttora sfuggenti. Il progetto EnhanceSex, finanziato dall’UE, ha sviluppato un sistema in vitro e in vivo per la generazione di progenitori gonadici murini a partire da cellule staminali embrionali che impiegherà per studiare le reti di regolazione genica alla base della determinazione del sesso dei mammiferi. Oltre alle conoscenze fondamentali in materia di sviluppo, i risultati del progetto forniranno importanti indizi sui disturbi legati allo sviluppo del sesso e apriranno nuove possibilità per concepire interventi inediti contro l’infertilità.
Obiettivo
During mammalian sex determination, the bipotential embryonic gonad adopts either testicular or ovarian cell fates. This process highly relies on precise expression of several pro-male versus pro-female factors, most of which are transcription factors (TFs) and signalling pathway components. Yet, we still do not understand the interplay and hierarchy among these factors, their direct target genes, the regulatory elements they bind to, nor do we have an in vitro system to address these questions.
We recently explored the complex gene expression regulation of Sox9, a key pro-male factor, and identified several active testis-specific enhancers. Remarkably, deletion of one of these led to XY male-to-female sex reversal in mice. The presence of several functional enhancers highlights the complex gene expression regulation present during sex determination, which we aim to address here in a systematic manner. Furthermore, we recently developed a system to generate mouse and human gonadal progenitors from embryonic stem cells. Building on our exciting results, we seek to decipher the gene regulatory networks governing mammalian sex determination using in vivo and in vitro approaches. This proposal will pursue three complementary aims: (i) Identify target genes of the key factors controlling gonad formation; (ii) Map the regulatory elements bound by these factors; (iii) Develop an in vitro organoid system to model testis development. Using cutting edge techniques as CUT&RUN ChIP-Seq, ATAC-Seq, Promoter Capture Hi-C, CRISPR genome editing, organoid culture and 3D scaffolding development, we will address the complex gene expression regulation governing sex determination. Insights gained from this basic research will shed light on cell fate decisions in general, allow better diagnosis of many patients with Disorders of Sex Development, and offer an in vitro system to study gonad development and function with implications for understanding and treating infertility.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
52900 Ramat Gan
Israele