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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hereditary persistence of α-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene
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Hereditary persistence of α-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene

机译：BALB / cJ小鼠肝脏中甲胎蛋白和H19表达的遗传持久性是由于在Zhx2基因中插入了逆转录病毒

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The α-fetoprotein (AFP) and H19 genes are transcribed at high levels in the mammalian fetal liver but are rapidly repressed postnatally. This repression in the liver is controlled, at least in part, by the Afr1 gene. Afr1 was defined >25 years ago when BALB/cJ mice were found to have 5- to 20-fold higher adult serum AFP levels compared with all other mouse strains; subsequent studies showed that this elevation was due to higher Afp expression in the liver. H19, which has become a model for genomic imprinting, was identified initially in a screen for Afr1-regulated genes. The BALB/cJ allele (Afr1~b) is recessive to the wild-type allele (Afr1~a), consistent with the idea that Afr1 functions as a repressor. By high-resolution mapping, we identified a gene that maps to the Afr1 interval on chromosome 15 and encodes a putative zinc fingers and homeoboxes (ZHX) protein. In BALB/cJ mice, this gene contains a murine endogenous retrovirus within its first intron and produces predominantly an aberrant transcript that no longer encodes a functional protein. Liver-specific overexpression of a Zhx2 transgene restores wild-type H19 repression on a BALB/cJ background, confirming that this gene is responsible for hereditary persistence of Afp and H19 in the livers of BALB/cJ mice. Thus we have identified a genetically defined transcription factor that is involved in developmental gene silencing in mammals. We present a model to explain the liver-specific phenotype in BALB/cJ mice, even though Afr1 is a ubiquitously expressed gene.
机译：甲胎蛋白（AFP）和H19基因在哺乳动物胎肝中高水平转录，但在出生后迅速被抑制。肝脏中的这种抑制作用至少部分地由Afr1基因控制。 Afr1定义于> 25年前，当时发现BALB / cJ小鼠的成年血清AFP水平比所有其他小鼠品系高5至20倍；随后的研究表明，这种升高是由于肝脏中更高的Afp表达所致。 H19，已成为基因组印迹的模型，最初是在Afr1调控基因的筛选中确定的。 BALB / cJ等位基因（Afr1〜b）对野生型等位基因（Afr1〜a）是隐性的，这与Afr1充当阻遏物的观点一致。通过高分辨率映射，我们确定了一个基因，该基因映射到15号染色体上的Afr1区间，并编码一个假定的锌指和同源盒（ZHX）蛋白。在BALB / cJ小鼠中，该基因在其第一个内含子中包含鼠类内源性逆转录病毒，并且主要产生异常的转录本，不再编码功能蛋白。 Zhx2转基因的肝脏特异性过表达恢复了BALB / cJ背景下的野生型H19抑制，证实该基因与BALB / cJ小鼠肝脏中Afp和H19的遗传性持久有关。因此，我们已经确定了在哺乳动物中涉及发育基因沉默的遗传定义的转录因子。我们提出了一个模型来解释BALB / cJ小鼠的肝脏特异性表型，即使Afr1是一个普遍表达的基因。

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