By Diane S. Krause, MD, PhD, and Stephanie Halene, MD
2008-05-01
Drs. Krause and Halene indicated no relevant conflicts of interest.
Johnnidis JB, Harris MH, Wheeler RT, et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451:1125-9.
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.
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.
- Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83-6.
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