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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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“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]
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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
Cheng, Y., Lai, F., Wang, X., Shang, D., Zou, J., Luo, M., Xia, X., Cheng, H., & Zhou, R. (2020) · Molecular Biology and Evolution · doi:10.1093/molbev/msaa195 · Cited by 14
“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
Smith, M., & Flodman, P. L. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2018.00101 · Cited by 18
Knocking Out Enhancers to Enhance Epigenetic Research
Duester, G. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.10.001 · Cited by 10
“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].”
BackgroundIchiyama‐Kobayashi, S., Hata, K., Wakamori, K., Takahata, Y., Murakami, T., Yamanaka, H., Takano, H., Yao, R., Uzawa, N., & Nishimura, R. (2024) · JCI Insight · doi:10.1172/jci.insight.175486 · Cited by 14
Feng, Q., Cui, N., Li, S., Cao, J., Chen, Q., & Wang, H.-Y. (2023) · The FASEB Journal · doi:10.1096/fj.202201596rrr · Cited by 12
3D genomics and its applications in precision medicine
Chen, M.-J., Liu, X., Liu, Q.-Y., Shi, D., & Li, H. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00428-x · Cited by 12
“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 15
Rore, H., Owen, N., Piña-Aguilar, R., Docherty, K., & Sekido, R. (2021) · Communications Biology · doi:10.1038/s42003-021-02322-8 · Cited by 12
Self-citationBagheri-Fam, S., Combes, A. N., Ling, C.-K., & Wilhelm, D. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa259 · Cited by 12
Koth, M. L., Garcia-Moreno, S. A., Novak, A., Holthusen, K. A., Kothandapani, A., Jiang, K.-E., Taketo, M., Nicol, B., Yao, H., Futtner, C., et al. (2020) · Development · doi:10.1242/dev.183814 · Cited by 12
Self-citationNamiRNA‐Enhancer Network: The Changing Era Challenge and Chance of miRNA
Chen, L., Liang, Y. J., Wei, H., Liu, M., Wu, J. C., Li, W., Li, W., Jin, Y., Li, Y., Zhao, W., et al. (2025) · Advanced Science · doi:10.1002/advs.202506830 · Cited by 8
ESR1 mediates estrogen-induced feminization of genetic male Chinese soft-shelled turtle
Li, P., Guo, Y., Jin, L., Liang, X., Chen, G., Sun, W., Xiao, L., Qian, G.-Y., & Ge, C.-T. (2022) · Biology of Reproduction · doi:10.1093/biolre/ioac088 · Cited by 11
“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
Atlas, G., Sreenivasan, R., & Sinclair, A. (2021) · Sexual Development · doi:10.1159/000519238 · Cited by 11
Sumiyama, K., & Tanave, A. (2020) · Development Growth & Differentiation · doi:10.1111/dgd.12671 · Cited by 15
The gene regulatory landscape driving mouse gonadal supporting cell differentiation
Stévant, I., Abberbock, E., Ridnik, M., Weiss, R., Swisa, L., Futtner, C. R., Maatouk, D. M., Lovell-Badge, R. H., Malysheva, V., & Gonen, N. (2025) · Science Advances · doi:10.1126/sciadv.adv1885 · Cited by 12
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 12
“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].”
BackgroundMilevskiy, M., Coughlan, H., Kane, S. R., Johanson, T. M., Kordafshari, S., Chan, W.-F., Tsai, M., Surgenor, E. E., Wilcox, S., Allan, R., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100424 · Cited by 10
“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
Wu, Y.-Q., Zhang, Y.-D., Liu, H., Gao, Y., Liu, Y.-Y., Chen, L., Liu, L., Irwin, D., Hou, C., Zhou, Z., et al. (2022) · Journal of Animal Science and Biotechnology · doi:10.1186/s40104-022-00726-y · Cited by 10
“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
Ridnik, M., Schoenfelder, S., & Gonen, N. (2021) · Sexual Development · doi:10.1159/000519244 · Cited by 14
Self-citationApplications of genome editing on laboratory animals
Galichet, C., & Lovell-Badge, R. H. (2021) · Laboratory Animals · doi:10.1177/0023677221993141 · Cited by 9
“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…”
MethodSelf-citationPletikosic, S. M. R., Starovlah, I. M., Miljković, D., Bajic, D. M., Čapo, I., Nef, S., Kostic, T. S., & Andrić, S. A. (2020) · Acta Physiologica · doi:10.1111/apha.13563 · Cited by 17
SOX9: a key transcriptional regulator in organ fibrosis
Li, Y., Xing, Y., Liu, N., Liu, B., & Wang, Z.-H. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1507282 · Cited by 9
Genomic technologies and the diagnosis of 46, XY differences of sex development
Idris, F. P., Sinclair, A. H., & Ayers, K. (2024) · Andrology · doi:10.1111/andr.13708 · Cited by 9
Metadata
- 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
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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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