In mammalian cells, the seed region of miRs (2-8 nucleotides)

is the primary determinant of target recognition. miRs bind to the 3′-untranslated regions of the target transcripts. The majority of miR/mRNA interactions require perfect complementarity between the seed region of miRs and their target mRNAs, whereas the pairing requirement outside the seed region is significantly less stringent.4 miRs sharing an identical sequence in the seed region are grouped into families, and miRs from the same family bind to and regulate the expression of essentially the same set of target mRNAs.5 Because the primary target recognition determinant is 7 to 8 nucleotides long in the https://www.selleckchem.com/products/SRT1720.html seed region, a single miR can potentially regulate hundreds of target mRNAs. This notion was further validated by a transcriptome analysis of tissues isolated from mice with targeted deletion of miRs. Among the multiple downstream mRNA targets, Pexidartinib cost the degree of regulation of each individual transcript is usually small (<2-fold).6, 7 It is believed that the additive/synergistic effect of regulating multiple mRNAs in the same pathway translates into significant biological outcomes and phenotypes. Similar to mRNA expression, miR expression has been found to be dysregulated in disease tissues in comparison with normal tissues. These dysregulated miRs represent a novel pool of therapeutic targets and biomarkers, including those in tissue fibrosis.8,

9 For example, the miR-29 family of miRs is down-regulated in a mouse model of cardiac fibrosis following myocardial infarction.

miR-29 is encoded in two separate tetracosactide genomic loci yielding four mature miRs (29a, 29b1, 29b2, and 29c). Multiple extracellular matrix (ECM) genes, including many isoforms of the collagen superfamily, are among the top-ranked predicted targets of miR-29. Experimentally, an miR-29 mimic led to repression whereas anti-miR-29 resulted in de-repression of many ECM genes in cultured cardiac fibroblasts. Despite the modest regulation of the individual gene, it has been postulated that the coordinated repression of multiple genes in the ECM pathway results in a strong biological outcome.10 In the current issue of Hepatology, Roderburg and colleagues11 set out to identify changes in miR expression in two different mouse models of liver fibrosis: carbon tetrachloride and bile duct ligation. As expected, many miRs were dysregulated in response to these fibrosis-inducing injuries. Among them, all three members of the miR-29 family were significantly down-regulated in response to both of these models. The authors further extended these observations by demonstrating miR-29 down-regulation in human cirrhotic liver samples. Because miRs are expressed in a cell type-specific manner, the authors also determined the relative expression levels of miR-29 in the four major liver cell types (hepatocytes, stellate cells, Kupffer cells, and endothelial cells).