Whole genome microarray analysis of gene expression in an imprinting center deletion mouse model of Prader-Willi syndrome
Whole genome microarray analysis of gene expression in an imprinting center deletion mouse model of Prader-Willi syndrome
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DOI：
10.1002/ajmg.a.31504
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发表时间：
2007-03-01
影响因子：
2
通讯作者：
White, Robert A.
中科院分区：
文献类型：
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作者：
Bittel, Douglas C.;Kibiryeva, Nataliya;White, Robert A.
Prader-Willi综合征(PWS)是由15q11-q13区域父系表达基因缺失引起的。为了进一步研究这种典型肥胖综合征的基因表达变化，我们使用全基因组微阵列研究了由父系来源的印记中心(IQ缺失(PWS IC缺失))导致的PWS小鼠模型。这些小鼠通常在出生后2-3天内死亡(反映出患有PWS的婴儿无法茁壮成长)，因此，从PWS IC缺失小鼠和正常胎仔出生后不到24小时的整个大脑提取的RNA进行了分析。在检查的45,000多个探针中，26,471个(59%)被检测到用于进一步分析，其中69个的表达发生了至少1.5倍的显著变化，错误发现率(FDR)为5%。在差异表达的基因中，有8个是印记的，来自PWS关键区(PWSCR)。在PWS IC小鼠中表达最高的三个基因是阿片黑素皮质素原(POMC)和两个功能未知的转录本。POMC基因敲除小鼠已被证明会患上肥胖症。因此，PWS IC缺失新生小鼠的POMC RNA升高可能是这些小鼠存活的一个重要遗传因素，因为它可能影响进食行为。有趣的是，Mc5r，一种已知直接对POMC表达变化做出反应的黑素皮质素受体，也上调了。已知Mc5r参与体温调节，据报道，体温调节在PWS婴儿中是异常的。这些观察结果支持Pomc和参与调节能量动态平衡的基因网络在PWS早期临床发现中的作用。其他值得注意的模式包括三个以前没有研究过的转录本，它们只在IC调控下从父亲的等位基因表达，包括AK013560、BB3144814和BB182944(它们的基因位于713号染色体上的小鼠PWSCR)。正如预期的那样，所有已知的来自PWSCR的父系表达基因在PWS IC缺失小鼠中的检测信号低于阈值，但在对照仔鼠中明显可检测到。用定量逆转录-聚合酶链式反应(RT-PCR)进一步检测了其中几个基因的表达状态。对这些小鼠基因表达的进一步分析可能会导致PWS影响的新途径。这些结果以及最近的其他报告表明，许多基因，特别是与能量代谢有关的基因表达的轻微变化的累积效应，导致了患有PWS的婴儿无法茁壮成长。(C)2006年Wiley-Liss，Inc.
Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes in the 15q11-q13 region. To further characterize alterations in gene expression in this classical obesity syndrome we used whole genome microarrays to study a PWS mouse model resulting from a paternally derived imprinting center (IQ deletion (PWS IC deletion). These mice die generally within 2-3 days of life (reflective of failure to thrive in infants with PWS) and therefore, the analysis was performed on RNA extracted from the whole brain of PWS IC deletion mice and normal littermates at less than 24 hr after birth. Of more than 45,000 probes examined, 26,471 (59%) were detected for further analysis, and 69 had a significant change in expression of at least 1.5-fold and a false discovery rate (FDR) of 5%. Eight of the genes with differential expression were imprinted and from the PWS critical region (PWSCR). The three genes with the highest expression in the PWS IC mice were pro-opiomelanocortin (Pomc) and two transcripts of unknown function. Pomc knockout mice have been shown to develop obesity. Therefore, elevated Pomc RNA in PWS IC deletion neonatal mice may be an important genetic factor in the survival of these mice as it may affect eating behavior. Interestingly, Mc5r, a melanocortin receptor known to directly respond to Pomc expression changes, was upregulated as well. Mc5r is known to be involved with thermoregulation which is reportedly abnormal in PWS infants. These observations support a role for Pomc and the network of genes involved in regulating energy homeostasis in the early clinical findings of failure to thrive observed in PWS. Other notable patterns include three previously unstudied transcripts that are expressed only from the paternal allele under regulatory control of the IC and include AK013560, BB3144814, and BB182944 (whose genes are located in the mouse PWSCR on chromosome 713). As expected, all the known paternally expressed genes from the PWSCR had detection signals below the threshold in the PWS IC deletion mice but were clearly detectable in control littermates. Several of the genes in this study were further examined by quantitative reverse transcription-PCR (RT-PCR) to confirm their expression status. Further analysis of gene expression in these mice may lead to novel pathways affected in PWS. These results, along with other recent reports, suggest that the cumulative effect of modest changes in expression of many genes, especially genes involved in energy metabolism, contribute to the failure to thrive of infants with PWS. (c) 2006 Wiley-Liss, Inc.