RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia
Open Access
- 22 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-16
- https://doi.org/10.1038/s41467-020-20848-z
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.Funding Information
- Bloodwise (15001, 15005)
- Cancer Research UK (C27943/A12788)
- Stichting Kinderen Kankervrij (329)
- Kay Kendall Leukaemia Fund (KKL1142)
- North of England Children’s Cancer Research Fund
This publication has 72 references indexed in Scilit:
- NCBI GEO: archive for functional genomics data sets—updateNucleic Acids Research, 2012
- Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor bindingLeukemia, 2012
- MATS: a Bayesian framework for flexible detection of differential alternative splicing from RNA-Seq dataNucleic Acids Research, 2012
- Epigenetics in Alternative Pre-mRNA SplicingCell, 2011
- SUPERFAMILY 1.75 including a domain-centric gene ontology methodNucleic Acids Research, 2010
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- SUPERFAMILY—sophisticated comparative genomics, data mining, visualization and phylogenyNucleic Acids Research, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- BLAT—The BLAST-Like Alignment ToolGenome Research, 2002
- Identification of protein coding regions by database similarity searchNature Genetics, 1993