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Sex reversal following deletion of a single distal enhancer of Sox9

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Science  14 Jun 2018:
eaas9408
DOI: 10.1126/science.aas9408

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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, Enh13, a 557–base pair element located 565 kilobases 5′, is essential to initiate mouse testis development; its deletion giving XY females with Sox9 transcript levels equivalent to 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 patients is associated with XY sex reversal, suggesting it is also critical in humans.

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