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

Denis Houzelstein (), Caroline Eozenou, Carlos F. Lagos, Maëva Elzaiat, Joelle Bignon-Topalovic, Inma Gonzalez, Vincent Laville, Laurène Schlick, Somboon Wankanit, Prochi Madon, Jyotsna Kirtane, Arundhati Athalye, Federica Buonocore, Stéphanie Bigou, Gerard S. Conway, Delphine Bohl, John C. Achermann, Anu Bashamboo and Ken McElreavey ()
Additional contact information
Denis Houzelstein: Human Developmental Genetics Unit
Caroline Eozenou: Human Developmental Genetics Unit
Carlos F. Lagos: Campus Los Leones
Maëva Elzaiat: Human Developmental Genetics Unit
Joelle Bignon-Topalovic: Human Developmental Genetics Unit
Inma Gonzalez: CNRS
Vincent Laville: CNRS
Laurène Schlick: Human Developmental Genetics Unit
Somboon Wankanit: Human Developmental Genetics Unit
Prochi Madon: Jaslok Hospital and Research Centre
Jyotsna Kirtane: Jaslok Hospital and Research Centre
Arundhati Athalye: Jaslok Hospital and Research Centre
Federica Buonocore: University College London
Stéphanie Bigou: Hôpital de la Pitié Salpêtrière
Gerard S. Conway: University College London
Delphine Bohl: Hôpital de la Pitié Salpêtrière
John C. Achermann: University College London
Anu Bashamboo: Human Developmental Genetics Unit
Ken McElreavey: Human Developmental Genetics Unit

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47162-2

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