Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration

Abstract

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. Conclusion 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.

Intestinal Epithelial Barrier Disruption through Altered Mucosal MicroRNA Expression in Human Immunodeficiency Virus and Simian Immunodeficiency Virus Infections

“…Consistent with our observations, previous studies have shown that depletion of miRNA processing enzymes or increased expression of miRNA exonucleases results in widespread decreases in miRNA expression (40)(41)(42)(43). To determine whether SIV infection altered expression of miRNA processing or degrading enzymes, we investigated the expression of three key proteins, AGO2, DICER1, and XRN2, using Western blot analysis.…”

“…MicroRNA targets were also enriched in several cell cycle and immune response pathways. Others have also reported that global downregulation of miRNA is linked to regenerative proliferation in the liver (43) and innate immune responses to pathogens (63). Although the precise effect of miRNA depletion in the GI tract during infection is unclear, these data suggest it might influence the derepression of the innate immune response during infection and cellular regeneration during viral insult.…”

“…Global miRNA depletion has been previously reported in the context of tissue injury, tissue regeneration, and disease (42,43,59,60). The global decrease in miRNA expression has been linked to a decrease in miRNA processing enzymes, such as DICER1, DROSHA, or AGO2.…”

“…MicroRNAs are known to regulate genes associated with intestinal epithelial membrane permeability, proliferation, and response to pathogens (15,16,43,63). Pathway analysis of three highly expressed miRNA, miR-16, -194, and -200c, in the gut mucosa revealed that many of the predicted and validated targets of these miRNA are involved in cell proliferation, differentiation, and defense.…”

Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers

“…Furthermore, the Dicer-targeting tumoursuppressive let7, which reduces Dicer protein levels in several cell lines (Tokumaru et al 2008), is downregulated by estrogen treatment (Qian et al 2011), constituting a mechanism for indirect upregulation of Dicer activity by estrogen modulation of miRs. Further, Dicer mRNA is targeted by estrogen-regulated miR-29a, miR-125, let7 and miR-21, and TRBP by let7 (Tokumaru et al 2008, Cochrane et al 2010, Shu et al 2011. From these studies (summarised in Table 2), it is clear that a pattern of regulation is increasingly observed whereby feedback loops involving steroid signalling permit the maintenance of hormoneregulated miR biogenesis at appropriate levels.…”