ABSTRACT
The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukemia. Here we show that the RUNX1/RUNX1T1 oncogene is a regulator of alternative RNA splicing in leukemic cells. The comprehensive analysis of RUNX1/RUNX1T1-associated splicing events identifies two principal mechanisms that underlie the differential production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start site selection, and (ii) direct or indirect control of the expression of genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5'-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals alternative splicing as an important component of transcriptome re-organization in leukemia by an aberrant transcriptional regulator.
Subject(s)
Alternative Splicing , Core Binding Factor Alpha 2 Subunit/genetics , Gene Expression Regulation, Leukemic , Leukemia, Myeloid/genetics , Oncogene Proteins, Fusion/genetics , RUNX1 Translocation Partner 1 Protein/genetics , Acute Disease , Cell Line, Tumor , Core Binding Factor Alpha 2 Subunit/metabolism , Gene Expression Profiling/methods , Humans , Leukemia, Myeloid/pathology , Models, Genetic , Oncogene Proteins, Fusion/metabolism , RNA Interference , RNA Isoforms/genetics , RNA Isoforms/metabolism , RUNX1 Translocation Partner 1 Protein/metabolism , Transcription Initiation SiteABSTRACT
Alternative splicing represents an important level of the regulation of gene function in eukaryotic organisms. It plays a critical role in virtually every biological process within an organism, including regulation of cell division and cell death, differentiation of tissues in the embryo and the adult organism, as well as in cellular response to diverse environmental factors. In turn, studies of the last decade have shown that alternative splicing itself is controlled by different mechanisms. Unfortunately, there is no clear understanding of how these diverse mechanisms, or determinants, regulate and constrain the set of alternative RNA species produced from any particular gene in every cell of the human body. Here, we provide a consolidated overview of alternative splicing determinants including RNA-protein interactions, epigenetic regulation via chromatin remodeling, coupling of transcription-to-alternative splicing, effect of secondary structures in pre-RNA, and function of the RNA quality control systems. We also extensively and critically discuss some mechanistic insights on coordinated inclusion/exclusion of exons during the formation of mature RNA molecules. We conclude that the final structure of RNA is pre-determined by a complex interplay between cis- and trans-acting factors. Altogether, currently available empirical data significantly expand our understanding of the functioning of the alternative splicing machinery of cells in normal and pathological conditions. On the other hand, there are still many blind spots that require further deep investigations.
Subject(s)
Alternative Splicing , Humans , Nucleic Acid Conformation , RNA/chemistryABSTRACT
Ample adaptive and functional opportunities of a living cell are determined by the complexity of its structural organisation. However, such complexity gives rise to a problem of maintenance of the coherence of inner processes in macroscopic interims and in macroscopic volumes which is necessary to support the structural robustness of a cell. The solution to this problem lies in multidimensional control of the adaptive and functional changes of a cell as well as its self-renewing processes in the context of environmental conditions. Six mechanisms (principles) form the basis of this multidimensional control: regulatory circuits with feedback loops, redundant inner diversity within a cell, multilevel distributed network organisation of a cell, molecular selection within a cell, continuous informational flows and functioning with a reserve of power. In the review we provide detailed analysis of these mechanisms, discuss their specific functions and the role of the superposition of these mechanisms in the maintenance of cell structural robustness in a wide range of environmental conditions.
