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Sex reversal following deletion of a single distal enhancer of Sox9

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Science  29 Jun 2018:
Vol. 360, Issue 6396, pp. 1469-1473
DOI: 10.1126/science.aas9408

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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

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.

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