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Genomewide microRNA down‐regulation as a negative feedback mechanism in the early phases of liver regeneration
Author(s) -
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.
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24421
Subject(s) - microrna , dicer , biology , liver regeneration , gene expression , gene , microbiology and biotechnology , gene expression profiling , regulation of gene expression , microarray , microarray analysis techniques , regeneration (biology) , transcriptome , drosha , genetics , rna interference , rna
The liver is one of the few organs that have the capacity to regenerate in response to injury. We carried out genomewide microRNA (miRNA) microarray studies during liver regeneration in rats after 70% partial hepatectomy (PH) at early and mid time points to more thoroughly understand their role. At 3, 12, and 18 hours post‐PH ∼40% of the miRNAs tested were up‐regulated. Conversely, at 24 hours post‐PH, ∼70% of miRNAs were down‐regulated. Furthermore, we established that the genomewide down‐regulation of miRNA expression at 24 hours was also correlated with decreased expression of genes, such as Rnasen , Dgcr8 , Dicer , Tarbp2 , and Prkra , associated with miRNA biogenesis. To determine whether a potential negative feedback loop between miRNAs and their regulatory genes exists, 11 candidate miRNAs predicted to target the above‐mentioned genes were examined and found to be up‐regulated at 3 hours 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 that some miRNAs could target multiple miRNA biogenesis genes simultaneously. We also demonstrated that overexpression of these miRNAs inhibited cell proliferation and modulated 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, whereas the subsequent genomewide 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. (H EPATOLOGY 2011;)