High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network

Abstract

High mobility group A (HMGA) proteins are oncofoetal chromatin architectural factors that are widely involved in regulating gene expression. These proteins are unique, because they are highly expressed in embryonic and cancer cells, where they play a relevant role in cell proliferation, stemness, and the acquisition of aggressive tumour traits, i.e., motility, invasiveness, and metastatic properties. The HMGA protein expression levels and activities are controlled by a connected set of events at the transcriptional, post-transcriptional, and post-translational levels. In fact, microRNA (miRNA)-mediated RNA stability is the most-studied mechanism of HMGA protein expression modulation. In this review, we contribute to a comprehensive overview of HMGA-targeting miRNAs; we provide detailed information regarding HMGA gene structural organization and a comprehensive evaluation and description of HMGA-targeting miRNAs, while focusing on those that are widely involved in HMGA regulation; and, we aim to offer insights into HMGA-miRNA mutual cross-talk from a functional and cancer-related perspective, highlighting possible clinical implications.

Keywords: High mobility group A; cancer; miRNA; post-transcriptional regulation.

Figure 1

Updated human HMGA1 transcripts structure from Ensembl Genome Browser (GRCh38.p12-GCF_000001405.38). From top to bottom: chromosome 6 (Chr 6) labelled with chromosome bands (white, black and grey), centromeres (pink) and the HMGA1 locus (green); the HMGA1 gene structure, showing the entire length of the region considered, the location on Chr 6 (NC_000006.12):34, 236, 485–34, 246, 445, the chromosome band (p21.31) and HMGA1 exons/introns (orange boxes/lines); and the HMGA1 coding transcripts. The empty boxes indicate UTRs, whereas the filled boxes indicate open reading frames (ORFs). Merged Ensembl/Havana and Ensembl protein-coding data are shown in orange and brown, respectively; HMGA1 protein-coding exons are highlighted in green.

Figure 2

Updated human HMGA2 transcripts structure from the Ensembl Genome Browser (GRCh38.p13-GCF_000001405.39). From top to bottom: chromosome 12 (Chr 12) labelled with chromosome bands (white, black, and grey), centromeres (pink), and the HMGA2 locus (green); the HMGA2 gene structure, showing the overall length of the region considered, the location on Chr 12 (NC_000012.12):65,823,216–65,968,410, the chromosome band (q14.3) and HMGA2 exons/introns (orange boxes/lines); and, HMGA2 coding transcripts. The empty boxes indicate UTRs, whereas the filled boxes indicate ORFs. Merged Ensembl/Havana and Ensembl protein-coding data are shown in orange and brown, respectively; HMGA2 protein-coding exons are highlighted in green.

Figure 3

The LIN28/let-7 circuitry. HMGA proteins are inserted in the connected regulatory network of the LIN28/let-7 axis, which contains several regulatory feedback loops.

Figure 4

An overview of HMGA1- and HMGA2-targeting miRNAs. (A) Comparison of the percentage distributions of experimentally validated and predicted HMGA1- and HMGA2-targeting miRNAs. (B) Venn diagrams of experimentally validated and predicted miRNAs targeting HMGA1 and HMGA2.