Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation.
Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation.
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GABA（A）受体亚基mRNA表达的复杂控制：变异，协方差和遗传调节。
DOI：
10.1371/journal.pone.0034586
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Williams RW
中科院分区：
文献类型：
--
作者：
Mulligan MK;Wang X;Adler AL;Mozhui K;Lu L;Williams RW
GABA - a型受体对快速抑制性神经传递至关重要，对脑功能至关重要。令人惊讶的是，受体亚基的表达在个体之间是高度可变的，但这种波动的原因和影响仍然未知。我们利用从小鼠和人类的多个脑区和平台收集的大量表达数据集研究了所有19个受体亚基的变异来源。Gabra1、Gabra2、Gabrb2、Gabrb3和Gabrg2的表达在大量BXD菌株中具有高度可变性和遗传性，这些菌株来自完全测序的亲本c57bl /6J和DBA/2J的杂交。这些亚基的遗传控制是复杂的，高度依赖于组织和mRNA区域。值得注意的是，这种高变异通常与表型差异无关。唯一的例外是Gabrb3，这是一个与焦虑有关的基因座。我们确定了影响亚基表达的上游遗传位点，包括5号染色体上调节海马中9个亚基表达的三个非连锁区域，这些区域也与多种表型相关。这些基因座内的候选基因包括Naaa、Nos1和Zkscan1。我们证实了包括主要通道gabra1、Gabrb2和gabrg2在内的亚基的高水平共表达，并在小鼠和人类中确定了该表达网络的保守成员。Gucy1a3， Gucy1b3和Lis1是涉及抑制信号传导的多个亚基的新和保守的结合物。最后，单个亚基的3 ' utr的近端和远端区域在两种物种中具有显著独立的表达模式。然而，即使在没有序列同源性的情况下，不同亚基的相应区域往往表现出一致的遗传控制和共表达（近端到近端或远端到远端）。我们的发现确定了调节亚基表达的新变异来源，并强调了生物网络缓冲4-100倍mRNA水平差异的非凡能力。
GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents—C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel—Gabra1, Gabrb2, and Gabrg2—and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3′ UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal), even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer 4–100 fold differences in mRNA levels.
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影响因子：
4.3
作者：
Huen, Michael S. Y.;Sy, Shirley M. H.;Chen, Junjie
通讯作者：
Chen, Junjie
DOI：
10.1073/pnas.0700153104
发表时间：
2007-07-24
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
3.4
作者：
Harvey, BH;Oosthuizen, F;Stein, DJ
通讯作者：
Stein, DJ
影响因子：
3.3
作者：
Bing, N;Hoeschele, I
通讯作者：
Hoeschele, I
影响因子：
7
作者：
Huang, Guo-Jen;Shifman, Sagiv;Flint, Jonathan
通讯作者：
Flint, Jonathan