A conserved NR5A1-responsive enhancer regulates SRY in testis-determination
Issued Date
2024-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-85189015262
Journal Title
Nature Communications
Volume
15
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.15 No.1 (2024)
Suggested Citation
Houzelstein D., Eozenou C., Lagos C.F., Elzaiat M., Bignon-Topalovic J., Gonzalez I., Laville V., Schlick L., Wankanit S., Madon P., Kirtane J., Athalye A., Buonocore F., Bigou S., Conway G.S., Bohl D., Achermann J.C., Bashamboo A., McElreavey K. A conserved NR5A1-responsive enhancer regulates SRY in testis-determination. Nature Communications Vol.15 No.1 (2024). doi:10.1038/s41467-024-47162-2 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/97879
Title
A conserved NR5A1-responsive enhancer regulates SRY in testis-determination
Author's Affiliation
Université Paris Cité
Institut Cochin
Jaslok Hospital and Research Centre
University College London
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Hôpital Universitaire Pitié Salpêtrière
UCL Great Ormond Street Institute of Child Health
Fundacion Ciencia para la Vida
CNRS Centre National de la Recherche Scientifique
Universidad San Sebastián
Institut Cochin
Jaslok Hospital and Research Centre
University College London
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Hôpital Universitaire Pitié Salpêtrière
UCL Great Ormond Street Institute of Child Health
Fundacion Ciencia para la Vida
CNRS Centre National de la Recherche Scientifique
Universidad San Sebastián
Corresponding Author(s)
Other Contributor(s)
Abstract
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.