Abstract
RUNX1 a member of the family of runt related transcription factors (RUNX), is essential for hematopoiesis. The expression of RUNX1 gene is controlled by two promoters; the distal P1 promoter and the proximal P2 promoter. Several isoforms of RUNX1 mRNA are generated through the use of both promoters and alternative splicing. These isoforms not only differs in their temporal expression pattern but also exhibit differences in tissue specificity. The RUNX1 isoforms derived from P2 are expressed in a variety of tissues, but expression of P1-derived isoform is restricted to cells of hematopoietic lineage. However, the control of hematopoietic-cell specific expression is poorly understood. Here we report regulation of P1-derived RUNX1 mRNA by RUNX1 protein. In silico analysis of P1 promoter revealed presence of two evolutionary conserved RUNX motifs, 0.6kb upstream of the transcription start site, and three RUNX motifs within 170bp of the 5’UTR. Transcriptional contribution of these RUNX motifs was studied in myeloid and T-cells. RUNX1 genomic fragment containing all sites show very low basal activity in both cell types. Mutation or deletion of RUNX motifs in the UTR enhances basal activity of the RUNX1 promoter. Chromatin immunoprecipitation revealed that RUNX1 protein is recruited to these sites. Overexpression of RUNX1 in non-hematopoietic cells results in a dose dependent activation of the RUNX1 P1 promoter. We also demonstrate that RUNX1 protein regulates transcription of endogenous RUNX1 mRNA in T-cell. Finally we show that SCL transcription factor is recruited to regions containing RUNX motifs in the promoter and the UTR and regulates activity of the RUNX1 P1 promoter in vitro. Thus, multiple lines of evidence show that RUNX1 protein regulates its own gene transcription.
Highlights
Runt-related transcription factor 1 (RUNX1) belongs to a family of three transcription factors
To identify potential transcription factors that regulates expression of RUNX1 mRNA derived from P1 promoter we performed in silico analysis
These results strongly suggest that RUNX motifs in the UTR inhibit activity of the RUNX1 P1 promoter
Summary
Runt-related transcription factor 1 (RUNX1) belongs to a family of three transcription factors. RHD is required for nuclear import, interaction with core binding factor β (CBFβ) for an efficient binding to target DNA, and physical and functional interaction with several other proteins to regulate gene transcription [1, 2]. Members of RUNX family are key regulators of lineage-specific gene expression and development of distinct organs [2, 3]: RUNX1 is essential for definitive hematopoiesis during embryonic development [4,5,6], RUNX2 is required for osteogenesis [7,8,9] and RUNX3 for development of gut and proprioceptive neurons of the dorsal root ganglia [10,11,12,13]. RUNX1 continue to play an important regulatory function in adult hematopoiesis and postnatal development
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