TY - JOUR
T1 - RUNX1 regulates the CD34 gene in haematopoietic stem cells by mediating interactions with a distal regulatory element
AU - Levantini, Elena
AU - Lee, Sanghoon
AU - Radomska, Hanna S.
AU - Hetherington, Christopher J.
AU - Alberich-Jorda, Meritxell
AU - Amabile, Giovanni
AU - Zhang, Pu
AU - Gonzalez, David A.
AU - Zhang, Junyan
AU - Basseres, Daniela S.
AU - Wilson, Nicola K.
AU - Koschmieder, Steffen
AU - Huang, Gang
AU - Zhang, Dong Er
AU - Ebralidze, Alexander K.
AU - Bonifer, Constanze
AU - Okuno, Yutaka
AU - Gottgens, Bertie
AU - Tenen, Daniel G.
PY - 2011/10/5
Y1 - 2011/10/5
N2 - 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.
AB - 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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U2 - 10.1038/emboj.2011.285
DO - 10.1038/emboj.2011.285
M3 - Article
C2 - 21873977
AN - SCOPUS:80053597496
SN - 0261-4189
VL - 30
SP - 4059
EP - 4070
JO - EMBO Journal
JF - EMBO Journal
IS - 19
ER -