The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease

Abstract

The miR-17/92 cluster is among the best-studied microRNA clusters. Interest in the cluster and its members has been increasing steadily and the number of publications has grown exponentially since its discovery with more than 1000 articles published in 2012 alone. Originally found to be involved in tumorigenesis, research work in recent years has uncovered unexpected roles for its members in a wide variety of settings that include normal development, immune diseases, cardiovascular diseases, neurodegenerative diseases and aging. In light of its ever-increasing importance and ever-widening regulatory roles, we review here the latest body of knowledge on the cluster's involvement in health and disease as well as provide a novel perspective on the full spectrum of protein-coding and non-coding transcripts that are likely regulated by its members.

Figure 1

Genomic representation of the human miR-17-92 cluster host gene (MIR17HG) and neighborhood genes on Chr 13q31.1-q33-1. (a) Genomic representation of genes located±10 kb around human MIR17HG. (b) Genomic representation of MIR17HG. Two transcripts are shown in light blue and individual members of the cluster represented as red rectangles. The two panels were created using the UCSC genome browser (http://genome.ucsc.edu/)

Figure 2

Members of the miR-17/92 cluster and its two paralogues miR-106a/363 and miR-106b/25 and their chromosomal location. Red: members of the miR-17 family; blue: members of the miR-18 family; green: members of the miR-19 family; orange: members of the miR-92 family

Figure 3

Sequences of the members of the miR-17/92 cluster (in bold face) and its two paralogues miR-106a/363 and miR-106b/25. The sequences are divided into four families according to the miRNA ‘seed' (the sequence spanning positions 2 through 7 inclusive counting from the 5′ end of the miRNA). The ‘seed' in each case is shown in boldface and is highlighted in blue

Figure 4

The transcriptional regulation and main targets of the miR-17/92 cluster and its paralogues. The transcriptional factors (TFs) in the left upper corner have been functionally validated; dark blue arrows indicate upregulation; black lines indicate repression. TFs in the blue ‘cloud' were identified by the ENCODE project and the relationship of most of them to the miR-17/92 cluster and its paralogues is putative. Blue TFs were validated previously and confirmed by ENCODE; red TFs putatively regulate the miR-17/92 cluster and at the same time are known to be targeted by cluster members; green TFs putatively regulate the miR-17/92 cluster and at the same time are known to be targeted by paralogue miR-106b/25. If the specific gene that is targeted by a miRNA is known, the repressor line ends at the gene; otherwise, it ends at the box boundary of the respective cell process

Figure 5

Differences between the ‘standard' and ‘expanded' model of miRNA targeting and the corresponding targetome. The seed of miR-18 is used as an example (bases at positions 2 through 7 inclusive). For the expanded model's G:U wobble examples and bulge examples, only a few representative cases are shown