Genome-wide MicroRNA Downregulation as a Negative Feedback Mechanism in the Early Phases of Liver Regeneration

摘要

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.ConclusionOur 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.