Sex reversal following deletion of a single distal enhancer of Sox9.
Nitzan GonenChris R FuttnerSophie WoodS Alexandra Garcia-MorenoIsabella M SalamoneShiela C SamsonRyohei SekidoFrancis PoulatDanielle M MaatoukRobin Lovell-BadgePublished in: Science (New York, N.Y.) (2018)
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.
Keyphrases
- transcription factor
- genome wide identification
- high throughput
- genome editing
- crispr cas
- cell fate
- genome wide
- stem cells
- binding protein
- dna methylation
- electronic health record
- copy number
- gene expression
- big data
- oxidative stress
- machine learning
- minimally invasive
- mass spectrometry
- deep learning
- molecularly imprinted