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Science. 2018 Jun 29;360(6396):1469-1473. doi: 10.1126/science.aas9408. Epub 2018 Jun 14.

Sex reversal following deletion of a single distal enhancer of Sox9.

Author information

1
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
2
Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA.
3
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
4
Department of Genetics and Development, Institute of Human Genetics, CNRS-University of Montpellier UMR9002, Montpellier, France.
5
Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA. robin.lovell-badge@crick.ac.uk.
6
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. robin.lovell-badge@crick.ac.uk.

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.

PMID:
29903884
PMCID:
PMC6034650
DOI:
10.1126/science.aas9408
[Indexed for MEDLINE]
Free PMC Article

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