Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration.
Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration.
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DOI：
10.1002/hep.24421
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发表时间：
2011-08
期刊：
影响因子：
13.5
通讯作者：
Steer, Clifford J.
中科院分区：
文献类型：
--
作者：
Shu, Jingmin;Kren, Betsy T.;Xia, Zhilian;Wong, Phillip Y. -P.;Li, Lihua;Hanse, Eric A.;Min, Michael X.;Li, Bingshan;Albrecht, Jeffrey H.;Zeng, Yan;Subramanian, Subbaya;Steer, Clifford J.
肝脏是为数不多的能够对损伤做出再生反应的器官之一。我们在70%PH后大鼠肝再生过程中的早期和中期时间点进行了全基因组miRNA微阵列研究，以更彻底地了解它们的作用。在PH后3、12和18小时，约40%的测试的miRNA被上调。相反，在PH后24小时，约70%的miRNA下调。此外，我们确定了在24小时时miRNA表达的全基因组下调也与诸如Rnasen、Dgcr 8、Dicer、Tarbp 2和Prkra等与miRNA生物发生相关的基因的表达降低相关。为了确定是否存在一个潜在的负反馈环之间的miRNA和它们的调控基因，11个候选的miRNA被预测为靶向上述基因进行了检查，发现在3小时后的PH上调。使用报告和功能分析，我们确定这些miRNA加工基因的表达可以调节的一个子集的miRNA和一些miRNA可以同时靶向多个miRNA生物合成基因。我们还证明，这些miRNA的过表达抑制细胞增殖和调节细胞周期在Huh-7人肝癌细胞和原代大鼠肝细胞。从这些观察结果，我们推测，在PH后的早期阶段选择性上调的miRNA参与启动和承诺的肝再生，而随后的全基因组下调的miRNA是需要有效的恢复肝细胞质量。我们的数据表明，miRNA的变化受到miRNA及其调控基因之间的负反馈环的调控，这可能在肝再生的稳态调控中发挥重要作用。
Liver is one of the few organs that have the capacity to regenerate in response to injury. We carried out genome-wide miRNA microarray studies during liver regeneration in rats after 70% PH at early and mid-time points to more thoroughly understand their role. At 3, 12 and 18 hrs post-PH ~ 40% of the miRNAs tested were up-regulated. Conversely, at 24 hrs post-PH, ~ 70% of miRNAs were down-regulated. Further, we established that the genome-wide down-regulation of miRNA expression at 24 hrs was also correlated with decreased expression of genes such as Rnasen, Dgcr8, Dicer, Tarbp2 and Prkra that are associated with miRNA biogenesis. To determine if a potential negative feedback loop between miRNAs and their regulatory genes existed, 11 candidate miRNAs which were predicted to target the above genes were examined and found to be up-regulated at 3 hrs post-PH. Using reporter and functional assays, we determined that expression of these miRNA-processing genes could be regulated by a subset of miRNAs and some miRNAs could target multiple miRNA biogenesis genes simultaneously. We also demonstrated that over-expression of these miRNAs inhibited cell proliferation and modulated the cell cycle in both Huh-7 human hepatoma cells and primary rat hepatocytes. From these observations, we postulated that selective up-regulation of miRNAs in the early-phase after PH was involved in the priming and commitment to liver regeneration, while the subsequent genome-wide down-regulation of miRNAs was required for efficient recovery of liver cell mass. Our data suggest that miRNA changes are regulated by negative feedback loops between miRNAs and their regulatory genes that may play an important role in the steady-state regulation of liver regeneration.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
4.5
作者：
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作者：
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DOI：
10.1152/ajpgi.00338.2009
发表时间：
2010-04-01
影响因子：
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作者：
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通讯作者：
McCaffrey, Anton P.
影响因子：
13.5
作者：
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Willenbring, Holger