New avenues of discovery have opened over the last decade with the discovery of microRNAs. MiRNAs are small RNAs of approximately 22 nucleotide length, which are transcribed from genomic DNA like messenger RNAs (mRNAs) but do not encode proteins. Their main function is that of gene regulation by targeting specific sequences in the 3’-untranslated region of mRNAs. It is estimated that the human genome encodes 300 to 500 miRNAs, and that ~30 percent of all genes are regulated by miRNAs. Differential expression of different miRNAs during hematopoiesis was first reported in 2003, and the specific regulatory functions of several miRNAs have since been elucidated.
The expression and processing of miRNAs has been reviewed in detail elsewhere. Initially a long, capped and polyadenylated, primary precursor (pri-miRNA) is transcribed, which is then cleaved into a hairpin-shaped pre-miRNA. The pre-miRNA is further processed into a single-stranded RNA of about 22 basepairs, which associates with the so-called RNA-induced silencing complex (RISC). This way the miRNA guides the RISC to specific mRNAs and thus regulates protein translation by targeting the mRNA for degradation or by translational silencing. The fact that a single miRNA can target multiple genes and a single gene can be targeted by multiple miRNAs allows for complex regulatory networks.
Several miRNAs with distinct roles in cell differentiation during development and in adult tissue maintenance have been discovered. For example, miR181 is expressed predominantly in lymphocytes and its expression promotes B-cell differentiation.1
In this paper, Johnnidis, et al. focus on miR223, which is expressed at low levels in hematopoietic stem and progenitor cells, and at higher levels in common myeloid progenitors with steadily rising expression with further granulocytic differentiation. In order to investigate the function of miR223, the investigators created mice that lacked expression of miR223 (knockout [KO] mice). These mice showed a surprising finding within the hematopoietic system. Since miR223 expression is upregulated with granulocytic differentiation, it was predicted to promote granulocytopoiesis and hence the mice were expected to lack granulocytes. Instead, these mice actually had higher numbers of granulocytes, which were hyper-responsive causing a hyperinflammatory state in the mice. The neutrophil count was twice that of wildtype (WT) mice, and this increase was found to be due to an increase in the number of granulocyte progenitors and enhanced neutrophil differentiation.
Using bio-informatics, the investigators found more than 100 potential target genes for miR223 but focused on mef2c, a transcription factor known to play a role in myelopoiesis, as it was the only gene with two conserved miR223 complimentary "seed" sites in its 3’UTR (untranslated region). Indeed, when the investigators created mice that lacked both miR223 and mef2c, they found that the mice had normal granulocyte numbers. However, the hyperinflammatory state persisted. Thus, while the increased neutrophil count of the miR223 KO mouse is caused at least in part through loss of downregulation of mef2c by miR223, a distinct mechanism is likely responsible for the hyperinflammatory state.
In Brief
The investigators have identified a role for miR223 in regulating granulocytopoiesis and granulocyte activation. MiR223 inhibits translation of Mef2c, a transcription factor that promotes myeloid progenitor proliferation and likely other factors, thereby keeping granulopoiesis "in check." It is intriguing that the increasing expression of miR223 with granulocytic differentiation appears to function as a built-in repressor or brake in the system, ultimately to prevent hyperinflammatory states, supporting the importance of the regulatory functions of miRNAs in hematopoiesis.
References
Competing Interests
Drs. Krause and Halene indicated no relevant conflicts of interest.
