The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia

Abstract

RNA molecules are a source of phenotypic diversity and an operating system that connects multiple genetic and metabolic processes in the cell. A dysregulated RNA network is a common feature of cancer. Aberrant expression of long non-coding RNA (lncRNA), micro RNA (miRNA), and circular RNA (circRNA) in tumors compared to their normal counterparts, as well as the recurrent mutations in functional regulatory cis-acting RNA motifs have emerged as biomarkers of disease development and progression, opening avenues for the design of novel therapeutic approaches. This review looks at the progress, challenges and future prospects of targeting cis-acting and trans-acting RNA elements for leukemia diagnosis and treatment.

Keywords: RNA; leukemia; pediatric leukemia.

Figure 1

Cis- and trans-acting RNA regulatory elements, mechanisms of function. Nucleus (a) Epigenetics, enhancers, transcription: transcribed and processed in the nucleus, most lncRNAs have nuclear localization and involved in chromatin remodeling and transcriptional regulation of gene expression; long intergenic non-coding RNAs (XIST, HOTTIP, ARIEL, LUNAR1 and others) interact with Polycomb complexes and other adapter proteins, form connections between transcriptional regulators and distal DNA sequences through DNA looping; lncRNAs transcribed from antisense to protein-coding genes DNA strands, e.g., AS-RBM15, PU.1-AS, regulate expression of these genes posttranscriptionally (d); both transcriptional and posttranscriptional mechanisms of action were described for some lncRNAs, e.g., HOTAIR, HOTAIRM1, UCA1, that regulate gene expression in their genomic locus (acting in cis), and distal genomic regions (acting in trans). (b) pre-mRNA splicing: cis-acting pre-mRNA motifs are recognized by trans-acting RNA and protein factors during pre-mRNA splicing. Inherited or somatic mutations in splicing regulatory sequences of pre-mRNA cause mRNA mis-splicing; alterations in untranslated 3′ and 5′ areas affect mRNA stability and translation; mutations in the spliceosomal U1 snRNA cause global mRNA mis-splicing and aberrant polyadenylation; lncRNA MALAT1 regulates phosphorylation of splicing factors; circular-RNA are formed through back-splicing of introns. (c) ncRNA maturation: germ line mutations in pri- and pre-miRNA-16-1-miR-15a abolish their maturation. Cytoplasm (d) mRNA translation: anti-sense lncRNAs (PU.1-AS and AS-RBM15) regulate expression of protein coding by either promoting or inhibiting translation; PU.1-AS and UCA1 lncRNAs form complexes with translational regulators (eIF4A, hnRNP1) which decreases mRNA translation efficiency; (e) mRNA stability: cis-acting regulatory elements in 3′ UTR determine mRNA stability; (f) miRNA sponging, endogenous competing lncRNA: HOTAIR and HOTAIRM1 sequester specific miRNAs; alterations in endogenous competing RNA influence miRNA levels. (g) protein levels: depletion of miR-20a, miR-125b, and miR206b by HOTAIRM1 increases mRNA stability and translation of autophagy regulators ULK1, E2F1, and DRAM2, and induces PML-RARA degradation.