ESPEYB16 6. DSD and Gender Dysphoria New Functions of (Old) Genes (5 abstracts)
6.3. Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9
Croft B , Ohnesorg T , Hewitt J , Bowles J , Quinn A , Tan J , Corbin V , Pelosi E , van den Bergen J , Sreenivasan R , Knarston I , Robevska G , Vu DC , Hutson J , Harley V , Ayers K , Koopman P & Sinclair A
Nat Commun. 2018 Dec 14;9(1):5319.
doi: 10.1038/s41467-018-07784-9. PubMed [citation] PMID: 30552336
Initial steps in the sex determination of the (human) testis depend on SRY regulating SOX9, but the exact mechanism that controls SOX9 expression remains unknown. These authors discovered four overlapping copy number variations (CNVs) upstream of SOX9 as the causes of sex reversal in two 46,XX DSD (with duplications) and two 46,XY DSD patients (with deletions). Prompted by this, they performed studies of these CNVs in cell systems and in mice, and found three essential regulatory elements for normal testis and male sex development, namely eSR-A, eSR-B and eALDI.
This study shows several interesting findings. First, loss of one copy of either of the two identified enhancers of SOX9 expression (eSR-A or eSR-B) resulted in abnormal testis development and 46,XY sex reversal. By contrast, the addition of one copy upregulated SOX9, thereby disturbing the ovarian program and resulted in 46,XX DSD. Second, it describes the exact mechanism how SF1, SRY and SOX9 regulate SOX9 expression. The three newly described enhancers of SOX9 transcription seem to work both synergistically and specifically to allow for controlled SOX9 expression and normal testis development. While eSR-A contains SF1 and SOX9 consensus binding sites, eSR-B and eALDI contain only SOX9 and SRY binding sites, respectively, but all are responsive to SF1 and SOX9. In addition, the female factor FOXL2 represses activity of all three elements. Third, these enhancers of SOX9 are found very far upstream of SOX9 and are missed in typical genetic sequencing studies for sex reversal. It is hypothesized that they come into contact to work in concert by chromatin looping. Lastly, humans are not mice. TESCO (the testis specific enhancer of SOX9 core element) has been shown to enhance SOX9 expression in rodents but not in men. But it seems that the equivalent with the same function in humans is eALDI.
In conclusion, alterations in regulatory regions beyond the currently known molecular network controlling gonadal determination may explain genetically unsolved patients with DSD.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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