Cooperative and individualistic functions of the microRNAs in the miR-23a~27a~24-2 cluster and its implication in human diseases

Abstract

The small RNA molecules of about 19-22 nucleotides in length, aptly called microRNAs, perform the task of gene regulation in the cell. Interestingly, till the early nineties very little was known about them but eventually, the microRNAs have become forefront in the area of research. The huge number of microRNAs plus each one of them targeting a vast number of related as well as unrelated genes makes them very interesting molecules to study. To add to the mystery of miRNAs is the fact that the same miRNA can have antagonizing role in two different cell types i.e. in one cell type; the miRNA promotes proliferation whereas in another cell type the same miRNA inhibits proliferation. Another remarkable aspect of the microRNAs is that many of them exist in clusters. In humans alone, out of 721 microRNAs known, 247 of them occur in 64 clusters at an inter-miRNA distance of less than 5000 bp. The reason for this clustering of miRNAs is not fully understood but since the miRNA clusters are evolutionary conserved, their significance cannot be ruled out. The objective of this review is to summarize the recent progress on the functional characterization of miR-23a~27a~24-2 cluster in humans in relation to various health and diseased conditions and to highlight the cooperative effects of the miRNAs of this cluster.

Figure 1

Multispecies alignment and genomic organization of miR-23a~27a~24-2 cluster. a. Alignment of the mature sequences of miR-23a, miR-27a and miR-24 among five species indicate that these miRNAs are highly conserved. b. The structure of the 2159 nucleotide pre-miR-transcript of hsa-mir-23a~27a~24-2, the structure of individual miRNAs shown is derived from the Mfold program [101]http://mfold.bioinfo.rpi.edu/cgi-bin/rna-form1.cgi with the input of their respective precursor sequences. The promoter region of this cluster spanning -603 to +36 is well characterized; it includes a GC rich region (-530 to -410) where transcription factors are predicted to bind and the transcription start site (TSS) spans 0 to 124 region. The poly-A tail is from 1752 to 1757.

Figure 2

Role of hsa-miR-23a in various pathological conditions. During cancer, repression of miR-23a by MYC leads to up-regulation of glutaminase (GLS) thus mediating glutamine metabolism which is important for bioenergetics and maintaining redox homeostasis in cancer cells. The transcription factor NFATc3 induces miR-23a which down-regulates MURF1, an anti-hypertrophic protein leading to cardiac hypertrophy. Also, in the conditions of heat induced stress, the expression level of miR-23a increases and by down-regulating MAFbx (an atrophic factor), it provides resistance to muscle atrophy.

Figure 3

Importance of hsa-miR-27a in oncogenesis, proliferation and differentiation. miR-27a induces oncogenesis by negatively regulating FOXO1 (transcription factor that regulates genes involved in apoptosis and cell cycle progression), RYBP (pro-apoptotic gene) and ZBTB10 (repressor of Sp proteins which are known to cause proliferative and angiogenic phenotype in cancer cells), mediates differentiation by down regulating RUNX1 (regulator of haematopoesis) and PPARγ and also promotes proliferation by targeting RYBP (pro-apoptotic gene).

Figure 4

Involvement of hsa-miR-24 in biological processes and the diseased states. The different biological processes and the diseased states where the role of hsa-miR-24 has been established are shown. The experimentally validated target genes of miR-24 are depicted along with the respective biological processes.

Figure 5

Workflow for the bioinformatics analysis of predicted targets of miR-23a, -27a and -24. Overview of the bioinformatics analysis of the TargetScan predicted targets of hsa-miR-23a, hsa-miR-27a and hsa-miR-24. The list of the pathways which crossed the p-value < 0.01 in PANTHER analysis is given in Additional File 3 and which crossed the p-value < 0.01 in GeneCodis analysis is given in Additional File 4. The pathways highlighted in yellow came out to be common among the enriched pathways of both PANTHER and GeneCodis analysis.

Figure 6

Speculated role of miR-23a~27a~24-2 cluster in regulation of Wnt Signaling. In normal circumstances, β-catenin protein is under the inhibitory effect of GSK-3β which leads to its degradation but when the Wnt signaling proteins bind to its receptors Frizzled and LRP-5 and -6; it leads to the activation of disheveled protein. This protein inhibits GSK-3β, thus preventing the degradation of β-catenin. Once the β-catenin is stabilized, it translocates to the nucleus and regulates the gene expression. In the various pathological conditions where this cluster is over expressed as is the case in many cancerous tissues, the Wnt genes; WNT3A and WNT4 could be targeted by miR-27a and miR-24 respectively, LRP5 and LRP6 by miR-23a and miR-27a respectively and FZD4 and FZD7 are targeted by both miR-23a and miR-27a. This leads to the inactivation of DVL1 protein. Also, DVL1 could itself be down-regulated by miR-27a. As a result, GSK-3β causes degradation of β-catenin, thus preventing its translocation to the nucleus and ultimately the transcription. To conserve the cells energy resources β-catenin associated genes like Cyclin D (targeted by miR-23a) and TCF7 (targeted by miR-24) are also inhibited. Among the other inhibitors of β-catenin (APC, Axin and PP2A), APC is targeted by miR-23a and PP2A by miR-27a, maybe these inhibitors are not required once GSK-3β is there to degrade β-catenin.