Abstract
CREB-binding protein (CBP, CREBBP, KAT3A) and its closely related paralogue p300 (EP300, KAT3B), together termed p300/CBP, are histone/lysine acetyl-transferases that control gene expression by modifying chromatin-associated proteins. Here, we report roles for both of these chromatin-modifying enzymes in mouse sex determination, the process by which the embryonic gonad develops into a testis or an ovary. By targeting gene ablation to embryonic gonadal somatic cells using an inducible Cre line, we show that gonads lacking either gene exhibit major abnormalities of XY gonad development at 14.5 dpc, including partial sex reversal. Embryos lacking three out of four functional copies of p300/Cbp exhibit complete XY gonadal sex reversal and have greatly reduced expression of the key testis-determining genes Sry and Sox9. An analysis of histone acetylation at the Sry promoter in mutant gonads at 11.5 dpc shows a reduction in levels of the positive histone mark H3K27Ac. Our data suggest a role for CBP/p300 in testis determination mediated by control of histone acetylation at the Sry locus and reveal a novel element in the epigenetic control of Sry and mammalian sex determination. They also suggest possible novel causes of human disorders of sex development (DSD).
Highlights
In mammals, the development of the bipotential embryonic gonad as a testis or ovary is determined by the presence or absence of the Y chromosome
Our data suggest a role for CBP/p300 in testis determination mediated by control of histone acetylation at the Sry locus and reveal a novel element in the epigenetic control of Sry and mammalian sex determination
To study the role of CBP and p300 in sex determination, conditional deletion in embryonic gonadal somatic cells was performed by crossing Cbpflox/flox or p300flox/flox mice with mice carrying Cbpflox or p300flox and tamoxifen-inducible Wt1CreERT2, in which Cre expression is driven by the endogenous Wt1 regulatory elements [41]
Summary
The development of the bipotential embryonic gonad as a testis or ovary is determined by the presence or absence of the Y chromosome. In XY embryos, the transient expression of Sry (sex determination region on Y chromosome) in somatic cells of the undifferentiated gonad between 10.5 dpc and 12.0 dpc triggers testis differentiation [1]. In XX gonads, the absence of SRY results in the activation of ovary-promoting pathways involving RSPO1/ WNT4/CTNNB1 and FOXL2 [4,5,6,7,8,9]. The timing of the expression of Sry is crucial for activation of the testis-determining pathway of gene expression; a Received: September 15, 2017.
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