期刊
EMBO JOURNAL
卷 30, 期 19, 页码 4059-4070出版社
WILEY
DOI: 10.1038/emboj.2011.285
关键词
CD34; gene regulation; haematopoietic stem cell; long-range chromatin looping; RUNX proteins
资金
- NIH [CA41456]
- Flight Attendant Medical Research Institute
- DFG [KO2155/1-1, 2-1, 2-2]
- Leukaemia and Lymphoma Research UK
- BBSRC [BB/I00050X/1] Funding Source: UKRI
- MRC [G0800784] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I00050X/1] Funding Source: researchfish
- Medical Research Council [G0800784, G0800784B] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0900729/1] Funding Source: researchfish
The transcription factor RUNX1 is essential to establish the haematopoietic gene expression programme; however, the mechanism of how it activates transcription of haematopoietic stem cell (HSC) genes is still elusive. Here, we obtained novel insights into RUNX1 function by studying regulation of the human CD34 gene, which is expressed in HSCs. Using transgenic mice carrying human CD34 PAC constructs, we identified a novel downstream regulatory element (DRE), which is bound by RUNX1 and is necessary for human CD34 expression in long-term (LT)-HSCs. Conditional deletion of Runx1 in mice harbouring human CD34 promoter-DRE constructs abrogates human CD34 expression. We demonstrate by chromosome conformation capture assays in LT-HSCs that the DRE physically interacts with the human CD34 promoter. Targeted mutagenesis of RUNX binding sites leads to perturbation of this interaction and decreased human CD34 expression in LT-HSCs. Overall, our in vivo data provide novel evidence about the role of RUNX1 in mediating interactions between distal and proximal elements of the HSC gene CD34. The EMBO Journal (2011) 30, 4059-4070. doi:10.1038/emboj.2011.285; Published online 26 August 2011
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