An Evolutionarily Conserved Mechanism for MicroRNA-223 Expression Revealed by MicroRNA Gene Profiling

Abstract

Many microRNAs (miRNAs) are evolutionarily conserved and have intriguing expression patterns. Tissue and/or time-specific expressions of some miRNAs are presumably controlled by unique cis-acting regulatory elements that coevolved with the miRNA sequences. Exploiting bioinformatics, we identified several miRNAs whose primary transcripts could be regulated by conserved genomic elements proximal to their transcription start sites. Such miRNAs include microRNA-223 (miR-223), which is reportedly controlled by a unique regulatory mechanism during granulopoiesis. Here, we define a mechanism distinct from that previously proposed to regulate miR-223 expression. We find that the mir-223 gene resembles a "myeloid gene" and might be driven by the myeloid transcription factors, PU.1 and C/EBPs. This mechanism is specified by the conserved proximal cis-regulatory element and might be common among different species. Hence, it needs to be considered that two distinct mechanisms that would play critical roles in myeloid functions and differentiation are actually concerned with the regulation of miR-223.

The role of microRNA in human leukemia: a review

“…Given that NFIA is in itself a target of miR-223, an auto-regulatory loop can be conceived. An alternative regulatory mechanism for this process has also been delineated by Fukao et al 36 These investigators found a PU.1 and C/EBPb-binding site capable of activating miR-223 transcription in mice. The PU.1-binding site is conserved in humans, making this a strong candidate for the control of miR-223 expression.…”

MicroRNAs and post-transcriptional regulation of skeletal development

“…In the same study, miR-223 was shown to target Nfia, an osteoclastogenesis suppressor that eventually negatively regulates the M-CSF receptor. Later, other groups validated these effects of miR-223 on osteoclastogenesis and revealed PU.1-binding sites in the miR-223 promoter (Fukao et al 2007, Sugatani & Hruska 2009, Shibuya et al 2013. Sugatani et al posited the existence of a feed-forward network whereby M-CSF induces PU.1 in osteoclast precursors, and PU.1 stimulates pri-miR-223 transcription, which, by downregulating the expression of Nfia, ultimately increases the levels of M-CSF receptor.…”

MicroRNA-223 coordinates cholesterol homeostasis

“…Although miR-223 was initially reported to be restricted to myeloid cells (14), multiple groups have since demonstrated functional miR-223 expression in nonmyeloid cell types, including hepatocytes (15). Hepatic miR-223 levels were found to be significantly increased upon ischemic/reperfusion injury (16) and decreased in hepatocellular carcinoma (17).…”