Functional conservation of Asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene Asx.
Functional conservation of Asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene Asx.
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DOI：
10.1371/journal.pone.0004750
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Wang QT
中科院分区：
文献类型：
--
作者：
Baskind HA;Na L;Ma Q;Patel MP;Geenen DL;Wang QT
多梳基团(PcG)和三胸基团(TrxG)蛋白分别调节组蛋白甲基化，以在靶基因座建立抑制性和活性染色质配置。这些染色质配置从母体细胞传给子代细胞，从而导致基因表达的可遗传变化。PcG和trxG蛋白的活性受一类特殊的蛋白质调节，这种蛋白质被称为三胸和息肉增强剂(ETP)。果蝇基因附加性梳(ASX)编码一种ETP蛋白，ASX的突变增强了PcG和trxG突变的表型。小鼠和人类的基因组都包含三个ASX同源物，ASX样蛋白1、2和3。为了了解哺乳动物ASX样蛋白(Asx1)的功能，我们从基因陷阱ES细胞系中获得了Asxl2突变小鼠。我们发现Asxl2基因TRAP在特定的组织中高水平表达，包括心脏、中轴骨骼、新皮质、视网膜、精原细胞和发育中的卵母细胞。基因陷阱突变部分是胚胎致死的，大约一半纯合子动物在出生前死亡。在胚胎发育中存活下来的纯合子比对照组小得多，寿命也缩短了。Asxl2−/−小鼠在轴骨中既表现出后移，又表现出前移，这表明Asxl2的缺失扰乱了PcG和trxG蛋白的活性。PcG相关的组蛋白修饰，组蛋白H3赖氨酸27的三甲基化，在Asx12−/−心脏中减少。尸检和组织学分析表明，突变小鼠的心脏变大，可能损害了心脏功能。我们的结果表明，小鼠Asxl2具有保守的ETP功能，在促进PcG和trxG活性方面具有双重作用。我们还揭示了Asxl2在心脏中的一个意想不到的作用，表明PcG/trxG系统可能参与了心功能的调节。
Polycomb-group (PcG) and trithorax-group (trxG) proteins regulate histone methylation to establish repressive and active chromatin configurations at target loci, respectively. These chromatin configurations are passed on from mother to daughter cells, thereby causing heritable changes in gene expression. The activities of PcG and trxG proteins are regulated by a special class of proteins known as Enhancers of trithorax and Polycomb (ETP). The Drosophila gene Additional sex combs (Asx) encodes an ETP protein and mutations in Asx enhance both PcG and trxG mutant phenotypes. The mouse and human genomes each contain three Asx homologues, Asx-like 1, 2, and 3. In order to understand the functions of mammalian Asx-like (Asxl) proteins, we generated an Asxl2 mutant mouse from a gene-trap ES cell line. We show that the Asxl2 gene trap is expressed at high levels in specific tissues including the heart, the axial skeleton, the neocortex, the retina, spermatogonia and developing oocytes. The gene trap mutation is partially embryonic lethal and approximately half of homozygous animals die before birth. Homozygotes that survive embryogenesis are significantly smaller than controls and have a shortened life span. Asxl2−/− mice display both posterior transformations and anterior transformation in the axial skeleton, suggesting that the loss of Asxl2 disrupts the activities of both PcG and trxG proteins. The PcG-associated histone modification, trimethylation of histone H3 lysine 27, is reduced in Asxl2−/− heart. Necropsy and histological analysis show that mutant mice have enlarged hearts and may have impaired heart function. Our results suggest that murine Asxl2 has conserved ETP function and plays dual roles in the promotion of PcG and trxG activity. We have also revealed an unexpected role for Asxl2 in the heart, suggesting that the PcG/trxG system may be involved in the regulation of cardiac function.
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