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Review
. 2023 Apr 14;6(2):104-113.
doi: 10.31662/jmaj.2023-0009. Epub 2023 Mar 24.

Roles of MicroRNAs in Disease Biology

Hiroshi I Suzuki  1   2   3
Affiliations
Review

Roles of MicroRNAs in Disease Biology

Hiroshi I Suzuki. JMA J. .

Abstract

Gene regulation by microRNAs (miRNAs) plays important roles in development, physiology, and disease. miRNAs are an abundant class of noncoding RNAs that are generated through multistep biosynthetic pathways and typically repress gene expression through target destabilization and translational inhibition. Complex interactions between miRNAs and target mRNAs are associated with characteristic molecular mechanisms, including miRNA cotargeting, target-directed miRNA degradation, and crosstalk with various RNA-binding proteins. Consistent with the broad influence on cellular function, miRNA deregulation is commonly observed in various diseases, particularly cancer, with both tumor-suppressive and oncogenic roles. Mutations in the miRNA biosynthetic pathway and several miRNA genes have been linked to diverse types of cancer and a subset of genetic diseases, respectively. Additionally, super-enhancers play important roles in the regulation of cell type-specific and disease-associated miRNAs. This review summarizes the molecular features of miRNA biogenesis and target regulation along with the roles of miRNAs in disease biology, with recent examples expanding the pathophysiological roles of miRNAs.

Keywords: biogenesis; cancer; genetic disease; microRNA; target regulation.

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Conflict of interest statement

None

Figures

Figure 1.
Figure 1.
Overview of the miRNA biogenesis pathway in mammalian cells. The canonical miRNA biogenesis pathway includes multiple steps, including the transcription of pri-miRNAs, DROSHA-mediated processing in the nucleus, export to the cytoplasm, DICER-mediated processing in the cytoplasm, loading onto AGO proteins, and RISC formation. Several sources of noncanonical miRNAs that are generated independently of DROSHA or DICER are known. Erythrocyte-specific miR-451 is generated via the cluster assistance mechanism of DROSHA processing and DICER-independent AGO2-mediated processing.
Figure 2.
Figure 2.
Effects of miRNA-mRNA interactions on target regulation and miRNA stability. a, Classification of canonical miRNA target sites. b, Effects of multiple miRNA target sites and extensive miRNA-mRNA target interactions on target repression and miRNA stability.
Figure 3.
Figure 3.
Mechanisms of miRNA dysregulation in cancer. a, The altered expression of tumor-suppressive or oncogenic miRNAs is induced by various mechanisms: (1) chromosomal abnormalities; (2) alterations in transcriptional regulation; (3) epigenetic mechanisms including super-enhancers; (4) mutations or modifications in miRNAs; and (5) dysregulation of the miRNA biogenesis pathway. b, Dysregulation of DICER in DICER1 syndrome. Several models of two-hit activation are shown. Various other scenarios have also been reported. c, Mutations in DROSHA and DGCR8 in Wilms tumors.
Figure 4.
Figure 4.
Pathogenic mutation of miR-140 in skeletal dysplasia and ceRBP effects. (Cited and modified from Grigelioniene G, Suzuki HI, Taylan F, et al. Gain-of-function mutation of microRNA-140 in human skeletal dysplasia. Nat Med. 2019;25(4):583-90 and Suzuki HI, Spengler RM, Grigelioniene G, et al. Deconvolution of seed and RNA-binding protein crosstalk in RNAi-based functional genomics. Nat Genet. 2018;50(5):657-61. Copyright of the figure belongs to the authors.) A seed region mutation in chondrocyte-specific miR-140 has been identified in spondyloepiphyseal dysplasia MIR140 type Nishimura (OMIM #618618). This mutation results in widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p (miR-140-5p-G) targets. Additionally, the miR-140-5p mutant seed competes with the Ybx1 RNA-binding protein for the overlapping binding sites.
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References

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