RUNX1 regulates the CD34 gene in haematopoietic stem cells by mediating interactions with a distal regulatory element

Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Center for Life Science, Boston, MA, USA.
The EMBO Journal (Impact Factor: 10.43). 08/2011; 30(19):4059-70. DOI: 10.1038/emboj.2011.285
Source: PubMed


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.

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Available from: Constanze Bonifer
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    • "This conformation, termed active chromatin hubs (ACHs), is mediated through the binding of transcription factors, and is only present when these genes are expressed. In hematopoietic stem cells (HSCs), the transcription factor RunxI is required for the interaction between the CD34 gene promoter and its downstream regulatory element [Levantini et al., 2011]. Transcription factor-mediated chromatin looping was demonstrated in erythroid cells. "
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