Sex reversal following deletion of a single distal enhancer of Sox9

Nitzan Gonen; Chris R. Futtner; Sophie Wood; S. Alexandra Garcia-Moreno; Isabella M. Salamone; Shiela C. Samson; Ryohei Sekido; Francis Poulat; Danielle M. Maatouk; Robin Lovell-Badge

doi:10.1126/science.aas9408

Sex reversal following deletion of a single distal enhancer of Sox9

Nitzan Gonen, Chris R. Futtner, Sophie Wood, S. Alexandra Garcia-Moreno, Isabella M. Salamone, Shiela C. Samson, Ryohei Sekido, Francis Poulat, Danielle M. Maatouk, Robin Lovell-Badge

Research output: Contribution to journal › Article › peer-review

160 Scopus citations

Abstract

Cell fate decisions require appropriate regulation of key genes. Sox9, a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer 13 (Enh13), a 557–base pair element located 565 kilobases 5′ from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.

Original language	English
Pages (from-to)	1469-1471
Number of pages	3
Journal	Science
Volume	360
Issue number	6396
DOIs	https://doi.org/10.1126/science.aas9408
State	Published - 29 Jun 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017 The Authors.

Funding

We dedicate this paper to the memory of Danielle M. Maatouk, a much-missed colleague. We are grateful to the Biological Research Facility, Genetic Modification Service, Advanced Sequencing Facility, and Experimental Histopathology Facility of the Francis Crick Institute and the Flow Cytometry Core at Northwestern University for technical assistance. We thank members of our labs for advice, support, and helpful comments. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001107), the U.K. Medical Research Council (FC001107), and the Wellcome Trust (FC001107), and by the U.K. Medical Research Council (U117512772). F.P. was funded by the Agence Nationale pour la Recherche (ANR blanc TestisDev). D.M.M. was funded by the Northwestern University School of Medicine.

Funders	Funder number
Northwestern University School of Medicine
U.K. Medical Research Council
National Institute of General Medical Sciences	T32GM008061
Wellcome Trust	U117512772
Francis Crick Institute
Cancer Research UK	FC001107
Agence Nationale de la Recherche
Agence Nationale pour le DÃ©veloppement de la Recherche en SantÃ©

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title = "Sex reversal following deletion of a single distal enhancer of Sox9",

abstract = "Cell fate decisions require appropriate regulation of key genes. Sox9, a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer 13 (Enh13), a 557–base pair element located 565 kilobases 5′ from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.",

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AU - Wood, Sophie

AU - Alexandra Garcia-Moreno, S.

AU - Salamone, Isabella M.

AU - Samson, Shiela C.

AU - Sekido, Ryohei

AU - Poulat, Francis

AU - Maatouk, Danielle M.

AU - Lovell-Badge, Robin

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AB - Cell fate decisions require appropriate regulation of key genes. Sox9, a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer 13 (Enh13), a 557–base pair element located 565 kilobases 5′ from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.

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Sex reversal following deletion of a single distal enhancer of Sox9

Abstract

Bibliographical note

Funding

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