MicroRNAs Control Hepatocyte Proliferation During Liver Regeneration

Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143, USA.
Hepatology (Impact Factor: 11.19). 05/2010; 51(5):1735-43. DOI: 10.1002/hep.23547
Source: PubMed

ABSTRACT MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G(1) to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH. CONCLUSION: Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration.

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Available from: Andrew Lee, Jun 20, 2014
    • "This transdifferentiation potential has been extensively studied in the context of regenerating the retina from the pigmented OC derivatives: RPE, ciliary body and iris (Luz- Madrigal et al., 2014; Tropepe et al., 2000; Wohl et al., 2012). miRNAs are central regulators of developmental processes including tissue regeneration (Song et al., 2010a; Thatcher et al., 2008) and several miRNAs have been documented to play key roles in maintaining cell fate in multiple lineages, as shown for miR-142 in the generation of hematopoietic stem cells and for miR-375 in the endocrine beta-cell lineage (Kaspi et al., 2014; Nimmo et al., 2013; Poy et al., 2004). "
    Journal of Cell Science 08/2015; 128(15). DOI:10.1242/jcs.177584 · 5.33 Impact Factor
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    • "Interestingly, as noted below, increased expression of miR-26a can suppress tumour growth arising from c-MYC overexpression (Kota et al., 2009), highlighting miR-26a as an important regulator of hepatocyte proliferation. Repression of miR-378 was also seen during the first 18 h after PH and miR-378 inhibited Odc1 (Table 1), which controls of DNA synthesis in hepatocytes (Song et al., 2010). Other studies have reported decreases in miRs-22a, 30b, let-7 family members, and, 122a, and 150 within 12–48 h after PH (Chen et al., 2011b; Yu et al., 2013). "
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    ABSTRACT: Since their discovery more than a decade ago microRNAs have been demonstrated to have profound effects on almost every aspect of biology. Numerous studies in recent years have shown that microRNAs have important roles in development and in the etiology and progression of disease. This review is focused on microRNAs and the roles they play in liver development, regeneration and liver disease; particularly chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, viral hepatitis and primary liver cancer. The key microRNAs identified in liver development and chronic liver disease will be discussed together with, where possible, the target messenger RNAs that these microRNAs regulate to profoundly alter these processes.
    The international journal of biochemistry & cell biology 04/2014; 54. DOI:10.1016/j.biocel.2014.04.002 · 4.24 Impact Factor
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    • "An essential contribution of miRNAs in this regenerative response has been supported by a recent study in which mice with genetic deletion of the DROSHA cofactor DGCR8, a factor required for microRNA biogenesis, exhibited markedly impaired hepatocyte proliferation after partial hepatectomy [17]. Although changes in expression of miRNAs after partial hepatectomy and in liver-graft models have been reported using array-based assays [17-24], only a small number of targets have been validated [22,23,25,26]. Importantly, the identification of the subset of mRNAs that are regulated by miRNAs in the regenerating liver is far from complete, in part due to the large number of possible mRNA:miRNA targeting relationships predicted by computational approaches. "
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    ABSTRACT: Background Validation of physiologic miRNA targets has been met with significant challenges. We employed HITS-CLIP to identify which miRNAs participate in liver regeneration, and to identify their target mRNAs. Results miRNA recruitment to the RISC is highly dynamic, changing more than five-fold for several miRNAs. miRNA recruitment to the RISC did not correlate with changes in overall miRNA expression for these dynamically recruited miRNAs, emphasizing the necessity to determine miRNA recruitment to the RISC in order to fully assess the impact of miRNA regulation. We incorporated RNA-seq quantification of total mRNA to identify expression-weighted Ago footprints, and developed a microRNA regulatory element (MRE) prediction algorithm that represents a greater than 20-fold refinement over computational methods alone. These high confidence MREs were used to generate candidate ‘competing endogenous RNA’ (ceRNA) networks. Conclusion HITS-CLIP analysis provide novel insights into global miRNA:mRNA relationships in the regenerating liver.
    BMC Genomics 04/2013; 14(1):264. DOI:10.1186/1471-2164-14-264 · 4.04 Impact Factor
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