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

Author

Listed:
  • Denis Houzelstein

    (Human Developmental Genetics Unit
    CNRS)

  • Caroline Eozenou

    (Human Developmental Genetics Unit
    CNRS
    CNRS)

  • Carlos F. Lagos

    (Campus Los Leones
    Fundación Ciencia & Vida)

  • Maëva Elzaiat

    (Human Developmental Genetics Unit
    CNRS)

  • Joelle Bignon-Topalovic

    (Human Developmental Genetics Unit
    CNRS)

  • Inma Gonzalez

    (CNRS
    and the Identity of Cells Unit)

  • Vincent Laville

    (CNRS
    Stem Cells and Development Unit
    Bioinformatics and Biostatistics Hub)

  • Laurène Schlick

    (Human Developmental Genetics Unit
    CNRS)

  • Somboon Wankanit

    (Human Developmental Genetics Unit
    CNRS
    Mahidol University)

  • 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
    Hôpital de la Pitié Salpêtrière)

  • John C. Achermann

    (University College London)

  • Anu Bashamboo

    (Human Developmental Genetics Unit
    CNRS)

  • Ken McElreavey

    (Human Developmental Genetics Unit
    CNRS)

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.

Suggested Citation

  • Denis Houzelstein & Caroline Eozenou & Carlos F. Lagos & Maëva Elzaiat & Joelle Bignon-Topalovic & Inma Gonzalez & Vincent Laville & Laurène Schlick & Somboon Wankanit & Prochi Madon & Jyotsna Kirtane, 2024. "A conserved NR5A1-responsive enhancer regulates SRY in testis-determination," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47162-2
    DOI: 10.1038/s41467-024-47162-2
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    References listed on IDEAS

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    1. Wouter Meuleman & Alexander Muratov & Eric Rynes & Jessica Halow & Kristen Lee & Daniel Bates & Morgan Diegel & Douglas Dunn & Fidencio Neri & Athanasios Teodosiadis & Alex Reynolds & Eric Haugen & Je, 2020. "Index and biological spectrum of human DNase I hypersensitive sites," Nature, Nature, vol. 584(7820), pages 244-251, August.
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    3. Brittany Croft & Thomas Ohnesorg & Jacqueline Hewitt & Josephine Bowles & Alexander Quinn & Jacqueline Tan & Vincent Corbin & Emanuele Pelosi & Jocelyn Bergen & Rajini Sreenivasan & Ingrid Knarston & , 2018. "Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    4. Wesley C. Warren & LaDeana W. Hillier & Jennifer A. Marshall Graves & Ewan Birney & Chris P. Ponting & Frank Grützner & Katherine Belov & Webb Miller & Laura Clarke & Asif T. Chinwalla & Shiaw-Pyng Ya, 2008. "Erratum: Genome analysis of the platypus reveals unique signatures of evolution," Nature, Nature, vol. 455(7210), pages 256-256, September.
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