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Gcn5乙酰转移酶活性丧失会导致小鼠胚胎出现神经管闭合缺陷和无脑畸形。

Loss of Gcn5 acetyltransferase activity leads to neural tube closure defects and exencephaly in mouse embryos.

作者信息

Bu Ping, Evrard Yvonne A, Lozano Guillermina, Dent Sharon Y R

机构信息

Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

出版信息

Mol Cell Biol. 2007 May;27(9):3405-16. doi: 10.1128/MCB.00066-07. Epub 2007 Feb 26.

DOI:10.1128/MCB.00066-07
PMID:17325035
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1899977/
Abstract

Gcn5 was the first transcription-related histone acetyltransferase (HAT) to be identified. However, the functions of this enzyme in mammalian cells remain poorly defined. Deletion of Gcn5 in mice leads to early embryonic lethality with increased apoptosis in mesodermal lineages. Here we show that deletion of p53 allows Gcn5(-/-) embryos to survive longer, but Gcn5(-/-) p53(-/-) embryos still die in midgestation. Interestingly, embryos homozygous for point mutations in the Gcn5 catalytic domain survive significantly longer than Gcn5(-/-) or Gcn5(-/-) p53(-/-) mice. In contrast to Gcn5(-/-) embryos, Gcn5(hat/hat) embryos do not exhibit increased apoptosis but do exhibit severe cranial neural tube closure defects and exencephaly. Together, our results indicate that Gcn5 has important, HAT-independent functions in early development and that Gcn5 acetyltransferase activity is required for cranial neural tube closure in the mouse.

摘要

Gcn5是首个被鉴定出的与转录相关的组蛋白乙酰转移酶（HAT）。然而，该酶在哺乳动物细胞中的功能仍未明确界定。小鼠中Gcn5的缺失会导致早期胚胎致死，并伴有中胚层谱系细胞凋亡增加。在此我们表明，p53的缺失使Gcn5（-/-）胚胎存活时间延长，但Gcn5（-/-）p53（-/-）胚胎仍在妊娠中期死亡。有趣的是，Gcn5催化结构域点突变的纯合胚胎比Gcn5（-/-）或Gcn5（-/-）p53（-/-）小鼠存活时间显著延长。与Gcn5（-/-）胚胎不同，Gcn5（hat/hat）胚胎未表现出细胞凋亡增加，但出现严重的颅神经管闭合缺陷和无脑畸形。总之，我们的结果表明，Gcn5在早期发育中具有重要的、不依赖HAT的功能，且Gcn5乙酰转移酶活性是小鼠颅神经管闭合所必需的。

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本文引用的文献

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The Drosophila histone acetyltransferase Gcn5 and transcriptional adaptor Ada2a are involved in nucleosomal histone H4 acetylation.果蝇组蛋白乙酰转移酶Gcn5和转录衔接子Ada2a参与核小体组蛋白H4的乙酰化。
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Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.谷氨酰胺扩增的ataxin-7改变TFTC/STAGA的募集和染色质结构，导致光感受器功能障碍。
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Using genomewide mutagenesis screens to identify the genes required for neural tube closure in the mouse.利用全基因组诱变筛选来鉴定小鼠神经管闭合所需的基因。
Birth Defects Res A Clin Mol Teratol. 2005 Sep;73(9):583-90. doi: 10.1002/bdra.20164.
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Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity.多聚谷氨酰胺扩展的脊髓小脑共济失调7型蛋白破坏正常的SAGA和SLIK组蛋白乙酰转移酶活性。
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Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration.多聚谷氨酰胺扩展的ataxin-7抑制STAGA组蛋白乙酰转移酶活性，从而导致视网膜变性。
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