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).
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Carré GA,Siggers P,Xipolita M,Brindle P,Lutz B,Wells S,Greenfield Adoi
10.1093/hmg/ddx398subject
Has Abstractpub_date
2018-01-01 00:00:00pages
190-198issue
1eissn
0964-6906issn
1460-2083pii
4627841journal_volume
27pub_type
杂志文章abstract::Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in the huntingtin protein. Full-length huntingtin is thought to be a predominant HEAT repeat alpha-solenoid, implying a role as a facilitator of macromolecular complexes. Here we have investigated huntingtin's domain structure an...
journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
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doi:10.1093/hmg/ddv489
更新日期:2016-02-01 00:00:00
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journal_title:Human molecular genetics
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journal_title:Human molecular genetics
pub_type: 杂志文章
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更新日期:2004-11-15 00:00:00
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