In mammalian foetal testes, SOX9 regulates expression of its target genes by binding to genomic regions with conserved signatures

Massilva Rahmoun (1, 2) , Rowena Lavery (3) , Sabine Laurent-Chaballier (4) , Nicolas Bellora (5) , Gayle K. Philip (6) , Moïra Rossitto (2) , Aleisha Symon (3) , Eric Pailhoux (7) , Florence Cammas (4) , Jessica Chung (6) , Stefan Bagheri-Fam (3) , Mark Murphy (8, 9) , Vivian Bardwell (9) , David Zarkower (9) , Brigitte Boizet-Bonhoure (2) , Philippe Clair (10, 11) , Vincent R. Harley (3) , Francis Poulat (2)

1 Immunopathologie de l'Inflammation
2 IGH - Institut de génétique humaine
3 Hudson Institute of Medical Research [Clayton]
4 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
5 IPATEC - Instituto Andino Patagónico de Tecnologías Biológicas y Geoambientales [Bariloche]
6 VLSCI, LAB-14, 700 Swanston Street, Carlton 3053, Victoria, Australia
7 BDR - Biologie du Développement et Reproduction
8 GERI - General Engineering Research Institute
9 UMN - University of Minnesota [Twin Cities]
10 DIMNP - Dynamique des interactions membranaires normales et pathologiques
11 IGF MGX - Institut de Génomique Fonctionnelle - Montpellier GenomiX

In mammalian embryonic gonads, SOX9 is required for the determination of Sertoli cells that orchestrate testis morphogenesis. To identify genetic networks directly regulated by SOX9, we combined analysis of SOX9-bound chromatin regions from murine and bovine foetal testes with sequencing of RNA samples from mouse testes lacking Sox9. We found that SOX9 controls a conserved genetic programme that involves most of the sex-determining genes. In foetal testes, SOX9 modulates both transcription and directly or indirectly sex-specific differential splicing of its target genes through binding to genomic regions with sequence motifs that are conserved among mammals and that we called 'Sertoli Cell Signature' (SCS). The SCS is characterized by a precise organization of binding motifs for the Sertoli cell reprogramming factors SOX9, GATA4 and DMRT1. As SOX9 biological role in mammalian gonads is to determine Sertoli cells, we correlated this genomic signature with the presence of SOX9 on chromatin in foetal testes, therefore equating this signature to a genomic bar code of the fate of foetal Sertoli cells. Starting from the hypothesis that nuclear factors that bind to genomic regions with SCS could functionally interact with SOX9, we identified TRIM28 as a new SOX9 partner in foetal testes.

Mots clés: foetal; genomic regions; target genes

Domaines: Sciences du Vivant [q-bio]; Génétique

Massilva Rahmoun, Rowena Lavery, Sabine Laurent-Chaballier, Nicolas Bellora, Gayle K. Philip, et al.. In mammalian foetal testes, SOX9 regulates expression of its target genes by binding to genomic regions with conserved signatures. Nucleic Acids Research, 2017, 45 (12), pp.7191 - 7211. ⟨10.1093/nar/gkx328⟩. ⟨hal-01596005⟩