A conserved NR5A1-responsive enhancer regulates SRY in testis-determination - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Nature Communications Année : 2024

A conserved NR5A1-responsive enhancer regulates SRY in testis-determination

Carlos F Lagos
Gerard S Conway
John C Achermann

Résumé

The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5’ regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY . Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.
Fichier principal
Vignette du fichier
s41467-024-47162-2.pdf (1.57 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte
Licence

Dates et versions

hal-04583192 , version 1 (22-05-2024)

Licence

Identifiants

Citer

Denis Houzelstein, Caroline Eozenou, Carlos F Lagos, Maëva Elzaiat, Joelle Bignon-Topalovic, et al.. A conserved NR5A1-responsive enhancer regulates SRY in testis-determination. Nature Communications, 2024, 15 (1), pp.2796. ⟨10.1038/s41467-024-47162-2⟩. ⟨hal-04583192⟩
0 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More