The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9
Open accessAbstract
Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9. Bioinformatic analysis identified three putative enhancers for SOX9 that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive SOX9 in the testis. This is the first study to identify SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively. These enhancers provide a hitherto missing link by which SRY activates SOX9 in humans, and establish SOX9 enhancer mutations as a significant cause of DSD.
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Cites
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339
Integrative analysis of 111 reference human epigenomes
Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. (2015) · Nature · doi:10.1038/nature14248 · Cited by 6,368
Mapping and analysis of chromatin state dynamics in nine human cell types
Ernst, J., Kheradpour, P., Mikkelsen, T. S., Shoresh, N., Ward, L. D., Epstein, C. B., Zhang, X., Wang, L., Issner, R., Coyne, M., et al. (2011) · Nature · doi:10.1038/nature09906 · Cited by 2,898
Enhancer redundancy provides phenotypic robustness in mammalian development
Osterwalder, M., Barozzi, I., Tissières, V., Fukuda-Yuzawa, Y., Mannion, B. J., Afzal, S. Y., Lee, E. A., Zhu, Y., Plajzer-Frick, I., Pickle, C. S., et al. (2018) · Nature · doi:10.1038/nature25461 · Cited by 642
Sex reversal following deletion of a single distal enhancer of Sox9
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. (2018) · Science · doi:10.1126/science.aas9408 · Cited by 235
Shadow Enhancers Are Pervasive Features of Developmental Regulatory Networks
Cannavò, E., Khoueiry, P., Garfield, D. A., Geeleher, P., Zichner, T., Gustafson, E. H., Ciglar, L., Korbel, J. O., & Furlong, E. E. M. (2016) · Current Biology · doi:10.1016/j.cub.2015.11.034 · Cited by 235
Cited by
Sex determination, gonadal sex differentiation, and plasticity in vertebrate species
Nagahama, Y., Chakraborty, T., Paul-Prasanth, B., Ohta, K., & Nakamura, M. (2021) · Physiological Reviews · doi:10.1152/physrev.00044.2019 · Cited by 346
Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale
Zhou, J. (2022) · Nature Genetics · doi:10.1038/s41588-022-01065-4 · Cited by 177
“The duplicated regions include an enhancer 33 in both maximal and minimal duplication variants that cause sex reversal, creating de novo contact between SOX9 and the new copy of the enhancer (Supplementary Fig.”
BackgroundChen, L.-F., Long, H. K., Park, M., Swigut, T., Boettiger, A. N., & Wysocka, J. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.03.009 · Cited by 66
Metadata
- Authors
- Croft, B., Ohnesorg, T., Hewitt, J., Bowles, J., Quinn, A., Tan, J., Corbin, V., Pelosi, E., van den Bergen, J., Sreenivasan, R., Knarston, I., Robevska, G., Vu, D. C., Hutson, J., Harley, V., Ayers, K., Koopman, P., & Sinclair, A.
- Venue
- Nature Communications
- Published
- 2018-12-14
- Volume
- 9
- Issue
- 1
- Pages
- 5319-5319
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2904231437
- Cited by
- 210
- References
- 6
- FWCI
- 9.58
- Type
- journal article
- Language
- en
- Open access
- gold
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- Croft, B., Ohnesorg, T., Hewitt, J., Bowles, J., Quinn, A., Tan, J., Corbin, V., Pelosi, E., van den Bergen, J., Sreenivasan, R., Knarston, I., Robevska, G., Vu, D. C., Hutson, J., Harley, V., Ayers, K., Koopman, P., & Sinclair, A. (2018). Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9. Nature Communications. https://doi.org/10.1038/s41467-018-07784-9
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