Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.
Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.
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DOI：
10.1161/circgenetics.109.902320
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Lusis AJ
中科院分区：
文献类型：
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作者：
Gargalovic PS;Erbilgin A;Kohannim O;Pagnon J;Wang X;Castellani L;LeBoeuf R;Peterson ML;Spear BT;Lusis AJ
我们以前在小鼠的15号染色体上定位了一个影响高密度脂蛋白胆固醇和甘油三酯水平的数量性状基因座，现在报告了潜在基因的鉴定。我们首先通过研究来自亲本菌株BALB/CJ和MRL/MPJ的一系列同源菌株对该基因座进行了精细定位。对基因表达和测序的分析以及转基因互补导致了锌指和同源盒2(ZX2)的鉴定，这是一种先前与α-胎儿蛋白的发育调控有关的转录因子。在BALB/CJ小鼠中，该蛋白的表达减少导致涉及脂蛋白代谢的几个基因的肝脏转录水平发生变化。最值得注意的是，zhx2突变导致未能抑制脂蛋白脂酶的表达，脂蛋白脂肪酶基因通常在成人肝脏中沉默，这在携带zhx2转基因的BALB/CJ小鼠中是正常的。我们鉴定了位于15号染色体数量性状基因座的基因，结果表明，该基因是影响脂蛋白代谢的关键基因的一种新的发育调节基因。
We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene. We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of α-fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene. We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.