Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes
Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes
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DOI：
10.1073/pnas.1534923100
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发表时间：
2003-10-14
影响因子：
11.1
通讯作者：
Goldstein, JL
中科院分区：
文献类型：
--
作者：
Horton, JD;Shah, NA;Goldstein, JL
脂肪酸和胆固醇的合成是细胞膜的组成部分，由三种膜结合转录因子调控：固醇调节元件结合蛋白(SREBP)-1a、-1c和-2。它们在肝脏中的功能已经在过表达每种SREBP同种异构体的转基因小鼠和由于SREBP裂解激活蛋白（SCAP）基因敲除而缺乏所有三种核SREBP的小鼠中得到了表征。SCAP是SREBP核定位所需的蛋白质。在这里，我们使用寡核苷酸阵列与来自三种小鼠肝脏的RNA杂交（转基因SREBP-1a，转基因SREBP-2，敲除SCAP）来鉴定肝脏中可能是srebp直接靶点的基因。共有1003个基因在转基因SREBP-1a小鼠肝脏中表达量增加，505个基因在转基因SREBP-2小鼠肝脏中表达量增加，343个基因在Scap（-/-）肝脏中表达量减少。33个基因子集满足SREBP转基因诱导和scap缺陷小鼠表达降低的严格组合标准。在这33个基因中，13个先前被确定为SREBP作用的直接靶点。在剩下的20个基因中，13个编码参与胆固醇代谢的酶或载体蛋白，3个参与脂肪酸代谢，4个与脂质代谢没有已知的联系。通过应用严格的组合标准，转基因/敲除方法可以鉴定出活性可能直接由一个转录因子家族控制的基因，在这种情况下是srebp。
The synthesis of fatty acids and cholesterol, the building blocks of membranes, is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs as a result of gene knockout of SREBP cleavage-activating protein (SCAP), a protein required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. A total of 1,003 genes showed statistically significant increased expression in livers of transgenic SREBP-1a mice, 505 increased in livers of transgenic SREBP-2 mice, and 343 showed decreased expression in Scap(-/-) livers. A subset of 33 genes met the stringent combinatorial criteria of induction in both SREBP transgenics and decreased expression in SCAP-deficient mice. Of these 33 genes, 13 were previously identified as direct targets of SREBP action. Of the remaining 20 genes, 13 encode enzymes or carrier proteins involved in cholesterol metabolism, 3 participate in fatty acid metabolism, and 4 have no known connection to lipid metabolism. Through application of stringent combinatorial criteria, the transgenic/knockout approach allows identification of genes whose activities are likely to be controlled directly by one family of transcription factors, in this case the SREBPs.