Speaker
Description
Comparative genomic studies between contemporary and extinct hominins revealed key evolutionary modifications, but their number has hampered a system level investigation of their combined roles in scaffolding modern traits. Through multi-layered integration we selected 15 genes carrying nearly fixed sapiens-specific protein-coding mutations and developed a scalable design of combinatorial CRISPR-Cas9 bidirectional perturbations to uncover their regulatory hierarchy in cortical brain organoids. Interrogating the effects of overexpression and downregulation for all gene pairs in all possible combinations, we defined their impact on transcription and differentiation and reconstructed their regulatory architecture. We uncovered marked cell type-specific effects, including the promotion of alternative fates and the emergence of interneuron populations, alongside a core subnetwork comprising KIF15, NOVA1, RB1CC1 and SPAG5 acting as central regulator across cortical cell types.
| Author(s) | Alessandro Vitriolo$1,2,3,†‡, Adrianos Skaros1,2,3†, Oliviero Leonardi 1,2,3, Veronica Finazzi 2,3, Marlene F. Pereira1,2,3, Filippo Prazzoli2,3, Sebastiano Trattaro1,2, Juan Moriano4,5, Daniele Capocefalo2,3, Carlo Emanuele Villa1,2,3, Michael Boettcher8*, Cedric Boeckx4,5,6,*‡7, Giuseppe Testa1,2,3*‡ |
|---|---|
| Affiliation(s) | 1. Department of Experimental Oncology, European Institute of Oncology IRCCS, Via Adamello 16, 20139, Milan, Italy 2. Department of Oncology and Hemato-Oncology, University of Milan, Via Santa Sofia 9, 20122, Milan, Italy 3. Human Technopole, Viale Rita Levi-Montalcini 1, 20157, Milan, Italy 4. University of Barcelona, 08007 Barcelona, Spain 5. University of Barcelona Institute of Complex Systems, 08007 Barcelona, Spain 6. University of Barcelona Institute of Neurosciences, 08007 Barcelona, Spain 7. Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain 8. Institute of Molecular Medicine, Section for Molecular Medicine of Signal Transduction, Faculty of Medicine, Universitätsmedizin Halle, Martin Luther University Halle-Wittenberg, 06120, Halle (Salle), Germany † These authors contributed equally ‡ Jointly supervised the work * Corresponding authors" |
