Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos
Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos
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DOI：
10.1002/dvdy.21479
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发表时间：
2008-04-01
影响因子：
2.5
通讯作者：
Dent, Sharon Y. R.
中科院分区：
文献类型：
--
作者：
Lin, Wenchu;Zhang, Zhijing;Dent, Sharon Y. R.
组蛋白乙酰转移酶（HATs）对基因激活很重要，它能改变染色质结构，促进转录蛋白与基因启动子结合。单个HAT在哺乳动物发育中的功能尚未明确界定。我们之前的研究表明，Gcn5作为一种典型的HAT，对早期胚胎的中胚层维持是必需的。纯合的Gcn5基因缺失胚胎在原肠胚形成后不久死亡，这妨碍了对Gcn5在发育后期功能的确定。我们在此报道了一种Gcn5（flox（neo））等位基因的产生，它只有部分功能，并产生一种亚效表型。该等位基因纯合的小鼠发生颅神经管闭合缺陷（NTDs）和无脑畸形的风险增加。在Gcn5（flox（neo）/Δ）胚胎中，这些缺陷的外显率甚至更高。这些结果表明，Gcn5的正常表达水平对小鼠神经管闭合至关重要，并预测这种HAT的突变可能与人类NTDs风险增加有关。
Histone acetyltransferases (HATs) are important to gene activation, altering chromatin structures to facilitate association of transcription proteins with gene promoters. The functions of individual HATs in mammalian developmental are not well defined. Our previous studies demonstrated that Gcn5, a prototypical HAT, is required for mesodermal maintenance in early embryos. Homozygous Gcn5 null embryos die soon after gastrulation, preventing determination of Gcn5 functions later during development. We report here the creation of a Gen5(flox(neo)) allele, which is only partially functional and gives rise to a hypomorphic phenotype. Mice homozygous for this allele had an increased risk of cranial neural tube closure defects (NTDs) and exencephaly. These defects were found at an even greater penetrance in Gcn5(flox(neo)/Delta) embryos. These results indicate that normal levels of Gcn5 expression are critical for neural tube closure in mice and predict that mutations in this HAT may be associated with increased risk of NTDs in humans.