MicroRNAs Regulate Mammalian Hematopoiesis

Figure 1. Hairpin precursor miRNA is cleaved by the RNAse III-like enzyme Dicer releasing the ~22 nucleotide miRNA. Associated with the multimolecular RISC complex, miRNAs target complementary mRNA species. In the case of miR-181, this promotes entry of Lin- progenitor cells into the B cell lineage.

Scientists appear on the verge of major revelations regarding long-overlooked and potentially fundamental mechanisms involving the regulation of mammalian gene expression. In 1993, it was demonstrated that a gene (lin-14) required for proper development of the nematode C. elegans encoded not a protein, but a small fragment of non-coding RNA.1 This small RNA fragment, capable of repressing the translation of its complementary gene (lin-14), was the first described microRNA (miRNA). Since these seminal discoveries, endo-genous miRNAs have been found in species ranging from plants to humans, with some conserved miRNAs crossing hundreds of millions of years of eukaryotic evolution.2 In the cytoplasm, miRNAs are cleaved from larger ~75 nucleotide (nt) hairpin-like precursors by Dicer, an RNAse III-like enzyme known to be critical during the earliest stages of mammalian development.3-5 The mature ~22 nt miRNAs associate with an RNAi-induced silencing complex (RISC) that can either repress or destroy target messenger RNAs depending on the degree of complementarity (Figure 1).6 Similar mechanisms are involved in powerful new gene silencing techniques utilizing small interfering RNAs (siRNAs) designed to target specific nucleotide sequences.2,7,8 Although many endogenous miRNAs have been identified in mammals, specific functions have remained largely undefined9-11 until now.

Studies showing tissue-specific and/or developmentally regulated expression of certain miRNAs underscore their potential role in biological processes.11-13 Chen et al. describe three conserved mammalian miRNAs, miR-181, miR-223, and miR-142s, that are differentially expressed in mouse hematopoietic tissues and in specific hematopoietic lineages.11 In vitro, ectopic expression of miR-181 in Lin- hematopoietic progenitors results in a doubling of cells entering the B cell lineage while having no effect on T cell numbers.11 In contrast, transfection of miR-223 or miR-142s leads to a 30 to 40% increase in cells entering the T cell lineage with little effect on B cell development.11 To assess whether similar processes might exist in vivo, miR-181-transfected hematopoietic progenitors were transplanted into lethally irradiated mice. It was shown that the numbers of cells entering the B cell lineage increased 50% when compared to control levels, while T cell numbers (primarily CD8+) decreased by 88%.11 It is likely that these results are due to the altered activity of miRNA-regulated genes associated with hematopoietic development, although the targets have yet to be identified.11 Hundreds of putative mammalian target genes involved in a broad range of biological processes have been predicted based on complementarity with identified miRNA species.14 Future studies will undoubtedly uncover which of these genes are indeed regulated by miRNAs, and reveal the scope with which endogenous small RNAs regulate mammalian gene expression.


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