Sex reversal following deletion of a single distal enhancer of Sox9
Open accessAbstract
Sox9 regulation during sex determination: Sex determination is regulated by the Sox9 gene. During testis differentiation, this gene is directly targeted by the product of the Y chromosome–encoded gene Sry . The regulatory region of Sox9 is complex, which is typical of genes with multiple roles in development. Gonen et al. find that a single far-upstream 557–base pair element is critical for up-regulating Sox9 . Without it, XY mice develop as females instead of males. The 557–base pair enhancer is conserved, likely to be relevant to human disorders of sex differentiation, and probably essential because it acts early in a time-critical process, and any failure allows ovary-specific factors to dominate. Science , this issue p. 1469
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Deletion of a relatively weak distal enhancer in the mouse Sox9 sex determination locus leads to sex reversal, while phenotypic effects of deleting stronger and more proximal Sox9 enhancers are much less pronounced.
“it was recently shown that deletion of a relatively weak distal enhancer in the mouse Sox9 sex determination locus leads to sex reversal, while the phenotypic effects of deleting stronger and more proximal Sox9 enhancers are much less pronounced [510].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [510]
The paper reports that deleting distal Enh13 causes complete XY sex reversal, while deleting the more proximal Enh14 did not alter the measured gonadal gene expression, and deleting TES had relatively little effect at E11.5 (indexed under Abstract; no page available). It describes robust reporter activity for Enh14, but does not establish the broader comparison that Enh13 is relatively weak and the more proximal enhancers are stronger as a group. (LLM, conf=0.84)
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Self-citationAn enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo
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“Sox9 gene is an important transcription factor expressed in embryonic and postnatal Sertoli cells of the testis, and its function is essential for the maintenance of testicular function (9, 10).”
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Self-citationTranscriptional autoregulation of zebrafish tbx6 is required for somite segmentation
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“Although it has been reported that deletion of a single enhancer causes severe developmental defects in some cases (Gonen et al., 2018; Sagai et al., 2005; Yanagisawa et al., 2003), enhancer redundancy appears to be a remarkably widespread hallmark in the transcriptional regulation of developmental genes (Frankel et a…”
BackgroundEnhancer-Promoter Communication: It’s Not Just About Contact
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The Foundational Framework of Tumors: Gametogenesis, p53, and Cancer
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DMRT1 is a testis-determining gene in rabbits and is also essential for female fertility
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“Conservation studies identified the homolog of Enhancer 13 in many mammalian species, including humans, cows, and rabbits, and DMRT1 consensus sites were predicted in all mammals examined except mice and rats ( Gonen et al., 2018 ).”
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Analysis of XX SRY-Negative Sex Reversal Dogs
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“[18]) leads to a development of a XX-SR phenotype; (ii) an enhancer, Enh13, responsible for activating SOX9 in XY mouse gonads has recently been identified [19].”
BackgroundSrag Regulates Autophagy via Integrating into a Preexisting Autophagy Pathway in Testis
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“2018) and deletion of a single distal enhancer of Sox9 in mice (Gonen et al. 2018) caused sex reversal.”
BackgroundExpanded Insights Into Mechanisms of Gene Expression and Disease Related Disruptions
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“In one case, knockout of one presumed testis enhancer for Sox9 had no effect on testis development, whereas knockout of another single testis enhancer reduced expression enough to result in reversal to an ovary fate [4].”
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3D genomics and its applications in precision medicine
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“In addition, knocking out the distal enhancer of Sox9 resulted in gender reversal in mice [78].”
BackgroundMethodWang, J., Wang, A., Tian, K., Hua, X., Zhang, B., Zheng, Y., Kong, X., Li, W., Xu, L., Wang, J., et al. (2022) · Cell Discovery · doi:10.1038/s41421-022-00421-2 · Cited by 14 · see citing works
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Self-citationNamiRNA‐Enhancer Network: The Changing Era Challenge and Chance of miRNA
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ESR1 mediates estrogen-induced feminization of genetic male Chinese soft-shelled turtle
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“SOX9 (SRY-related HMG box gene 9), a direct target of SRY, is pivotal in vertebrate sex determination [45].”
BackgroundTargeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development
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Sumiyama, K., & Tanave, A. (2020) · Development, Growth and Differentiation · doi:10.1111/dgd.12671 · Cited by 11 · see citing works
The gene regulatory landscape driving mouse gonadal supporting cell differentiation
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Self-citationCis-Regulatory Elements in Mammals
Liu, X., Chen, M., Qu, X., Liu, W., Dou, Y., Liu, Q., Shi, D., Jiang, M., & Li, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010343 · Cited by 10 · see citing works
“Gonen et al. identified a direct reciprocal enhancer 13 (Enh13) with Sox9 and when it was knocked down in the XY chromosome of male mouse, and they showed that the expression of Sox9 was significantly reduced and the ovaries as well as other female genitalia features grew in the male mouse [93].”
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“10,11 The mammary gland is composed of an epithelial ductal tree that undergoes dramatic morphogenesis across the different developmental phases.”
BackgroundGenome-wide identification of functional enhancers and their potential roles in pig breeding
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“Previous studies found that enhancers have crucial roles in sexual development in mammals and that duplication or deletion of some of these enhancers could result in sex reversal [6, 7].”
BackgroundCis-Regulatory Control of Mammalian Sex Determination
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Self-citationApplications of genome editing on laboratory animals
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“For example, CRISPR/ Cas9-mediated deletion of enhancers of the Sox9 gene have given insights in different human conditions; deletion of the rib-cage-specific enhancer to model human acampomelic campomelic dysplasia and campomelic dysplasia syndromes(119) or deletion of testis-specific enhancers to model disorders of…”
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SOX9: a key transcriptional regulator in organ fibrosis
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Genomic technologies and the diagnosis of 46, XY differences of sex development
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- Authors
- Gonen, N., Futtner, C. R., Wood, S., Garcia-Moreno, S. A., Salamone, I. M., Samson, S. C., Sekido, R., Poulat, F., Maatouk, D. M., & Lovell-Badge, R.
- Affiliations
- The Francis Crick Institute (GB)
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA.
- Northwestern University (US)
- University of Aberdeen (GB)
- Department of Genetics and Development, Institute of Human Genetics, CNRS-University of Montpellier UMR9002, Montpellier, France.
- Corresponding author
- Maatouk, Danielle M.
- Lovell-Badge, Robin
- ORCID
- Venue
- Science
- Published
- 2018-06-29
- Volume
- 360
- Issue
- 6396
- Pages
- 1469-1473
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6034650
- OpenAlex
- W2808131961
- Cited by
- 235
- References
- 46
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 24 · 2023: 27 · 2022: 42 · 2021: 33 · 2020: 28 · 2019: 32 · 2018: 16
- FWCI
- 16.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Northwestern Medical Faculty Foundation, Inc.
- Francis Crick Institute
- Agence Nationale de la Recherche
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SOX9, sex determination, sex reversal, distal enhancers, SRY, testicular differentiation, XY females, disorders of sex development, gene expression regulation
- MeSH terms
- Animals, Enhancer Elements, Genetic, Female, Gonadal Dysgenesis, 46,XY, Humans, Male, Testis, Conserved Sequence, Sequence Deletion, Sex Determination Processes, Transcription Initiation Site, Mice, Sex-Determining Region Y Protein, SOX9 Transcription Factor
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