Runx1 exon 6–related alternative splicing isoforms differentially regulate hematopoiesis in mice
| Autor: | Kentson Lam, Yi-Jou Huang, Ming Yan, James R. Downing, Yukiko Komeno, Miao Chia Lo, Dong-Er Zhang, Shinobu Matsuura, Daniel G. Tenen |
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| Rok vydání: | 2014 |
| Předmět: |
Gene isoform
Cells Transgene Molecular Sequence Data Clinical Sciences Immunology Sequence Homology Mice Transgenic Cardiorespiratory Medicine and Haematology Biology Inbred C57BL Biochemistry Transgenic Paediatrics and Reproductive Medicine Mice Transactivation Exon chemistry.chemical_compound Genetics Animals Humans Protein Isoforms 2.1 Biological and endogenous factors Cells Cultured Regulation of gene expression Cultured Base Sequence Alternative splicing Exons Cell Biology Hematology Stem Cell Research Molecular biology Hematopoiesis Mice Inbred C57BL HEK293 Cells Gene Expression Regulation RUNX1 chemistry Core Binding Factor Alpha 2 Subunit RNA splicing Stem Cell Research - Nonembryonic - Non-Human RNA Splice Sites |
| Zdroj: | Blood, vol 123, iss 24 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | RUNX1 is an important transcription factor for hematopoiesis. There are multiple alternatively spliced isoforms of RUNX1. The best known isoforms are RUNX1a from use of exon 7A and RUNX1b and c from use of exon 7B. RUNX1a has unique functions due to its lack of C-terminal regions common to RUNX1b and c. Here, we report that the ortholog of human RUNX1a was only found in primates. Furthermore, we characterized 3 Runx1 isoforms generated by exon 6 alternative splicing. Runx1bEx6(-) (Runx1b without exon 6) and a unique mouse Runx1bEx6e showed higher colony-forming activity than the full-length Runx1b (Runx1bEx6(+)). They also facilitated the transactivation of Runx1bEx6(+). To gain insight into in vivo functions, we analyzed a knock-in (KI) mouse model that lacks isoforms Runx1b/cEx6(-) and Runx1bEx6e. KI mice had significantly fewer lineage-Sca1(+)c-Kit(+) cells, short-term hematopoietic stem cells (HSCs) and multipotent progenitors than controls. In vivo competitive repopulation assays demonstrated a sevenfold difference of functional HSCs between wild-type and KI mice. Together, our results show that Runx1 isoforms involving exon 6 support high self-renewal capacity in vitro, and their loss results in reduction of the HSC pool in vivo, which underscore the importance of fine-tuning RNA splicing in hematopoiesis. |
| Databáze: | OpenAIRE |
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