The Francis Crick Institute
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Sex reversal following deletion of a single distal enhancer of Sox9

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journal contribution
posted on 2020-07-27, 11:28 authored by Nitzan Gonen, Chris R Futtner, Sophie Wood, S Alexandra Garcia-Moreno, Isabella M Salamone, Shiela C Samson, Ryohei Sekido, Francis Poulat, Danielle M Maatouk, Robin Lovell-Badge
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.