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

Nitzan Gonen,Francis Poulat,S Alexandra Garcia-Moreno,Shiela C Samson,Danielle M Maatouk,Ryohei Sekido,Isabella M Salamone,Sophie Wood,Robin Lovell-Badge,Chris R Futtner

doi:10.1126/science.aas9408

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.

Highlights

Y elements required for each are often interspersed and necessitate dynamic alterations in chromatin conformation [1, 2]
Most putative enhancers discovered by DNaseI-seq were evident in the E13.5 XY ATAC-seq data, we used this to include two more in the in vivo screen; Enhancer (Enh) 1 and 14
DNaseI-seq, ATAC-seq, and H3K27ac ChIP-seq all suggest that this enhancer is active and open only in Sertoli cells

Summary

Introduction

Y elements required for each are often interspersed and necessitate dynamic alterations in chromatin conformation [1, 2]. Targeted deletion of TES or TESCO reduced Sox9 expression levels in the early and postnatal mouse testis to about 45% of normal but did not result in XY female development [17].

Results

Conclusion