Fibrinogen gene regulation
Fibrinogen gene regulation
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DOI：
10.1160/th12-04-0273
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发表时间：
2012-09-01
影响因子：
6.7
通讯作者：
Neerman-Arbez, Marguerite
中科院分区：
文献类型：
--
作者：
Fish, Richard J.;Neerman-Arbez, Marguerite
纤维蛋白原的 A α、B β 和 γ 多肽链由人类第四号染色体上的三基因簇编码。纤维蛋白原基因 (FGB-FGA-FGG) 几乎只在肝细胞中表达，在肝细胞中协调它们的输出以确保每条链有足够的 mRNA 库并维持丰富的血浆纤维蛋白原蛋白水平。纤维蛋白原基因表达受近端启动子的活性控制，该启动子含有肝细胞转录因子的结合位点，包括响应急性期炎症刺激影响纤维蛋白原转录的蛋白质。纤维蛋白原基因簇还含有顺式调控元件；通过序列保守性和功能基因组学鉴定具有肝脏活性的增强子序列。虽然该基因簇的转录控制在生物学上令人着迷，但了解纤维蛋白原基因调控的医学动力源于心血管疾病风险与高水平循环纤维蛋白原的关联。在一般人群中，这一水平约为 1.5 至 3.5 克/升。个体之间的这种差异受到基因型的影响，这表明存在影响纤维蛋白原调节位点的纤维蛋白原水平的遗传变异。因此，纤维蛋白原基因如何调控的完整图景将指向调控变异的新来源。在这篇综述中，我们讨论了近端启动子和增强子对纤维蛋白原基因的调控、急性期模拟的影响、miRNA 的转录后调控以及遗传研究中发现的功能调控变异。最后，我们根据理解染色体结构的最新进展讨论了纤维蛋白原基因座，并提出了研究控制纤维蛋白原表达机制的未来方向。
The A alpha, B beta and gamma polypeptide chains of fibrinogen are encoded by a three gene cluster on human chromosome four. The fibrinogen genes (FGB-FGA-FGG) are expressed almost exclusively in hepatocytes where their output is coordinated to ensure a sufficient mRNA pool for each chain and maintain an abundant plasma fibrinogen protein level. Fibrinogen gene expression is controlled by the activity of proximal promoters which contain binding sites for hepatocyte transcription factors, including proteins which influence fibrinogen transcription in response to acute-phase inflammatory stimuli. The fibrinogen gene cluster also contains cis regulatory elements; enhancer sequences with liver activities identified by sequence conservation and functional genomics. While the transcriptional control of this gene cluster is fascinating biology, the medical impetus to understand fibrinogen gene regulation stems from the association of cardiovascular disease risk with high level circulating fibrinogen. In the general population this level varies from about 1.5 to 3.5 g/l. This variation between individuals is influenced by genotype, suggesting there are genetic variants contributing to fibrinogen levels which reside in fibrinogen regulatory loci. A complete picture of how fibrinogen genes are regulated will therefore point towards novel sources of regulatory variants. In this review we discuss regulation of the fibrinogen genes from proximal promoters and enhancers, the influence of acute-phase simulation, post-transcriptional regulation by miRNAs and functional regulatory variants identified in genetic studies. Finally, we discuss the fibrinogen locus in light of recent advances in understanding chromosomal architecture and suggest future directions for researching the mechanisms that control fibrinogen expression.