Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche.
Fitch, Simon R
de Bruijn, Marella F
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Fitch, S. R., Kapeni, C., Tsitsopoulou, A., Wilson, N., Gottgens, B., de Bruijn, M. F., & Ottersbach, K. (2020). Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche.. IUBMB life, 72 (1), 45-52. https://doi.org/10.1002/iub.2184
Runx1 is an important haematopoietic transcription factor as stressed by its involvement in a number of haematological malignancies. Furthermore, it is a key regulator of the emergence of the first haematopoietic stem cells (HSCs) during development. The transcription factor Gata3 has also been linked to haematological disease and was shown to promote HSC production in the embryo by inducing the secretion of important niche factors. Both proteins are expressed in several different cell types within the aorta-gonads-mesonephros (AGM) region, in which the first HSCs are generated; however, a direct interaction between these two key transcription factors in the context of embryonic HSC production has not formally been demonstrated. In this current study, we have detected co-localisation of Runx1 and Gata3 in rare sub-aortic mesenchymal cells in the AGM. Furthermore, the expression of Runx1 is reduced in Gata3-/- embryos, which also display a shift in HSC emergence. Using an AGM-derived cell line as a model for the stromal microenvironment in the AGM and performing ChIP-Seq and ChIP-on-chip experiments, we demonstrate that Runx1, together with other key niche factors, is a direct target gene of Gata3. In addition, we can pinpoint Gata3 binding to the Runx1 locus at specific enhancer elements which are active in the microenvironment. These results reveal a direct interaction between Gata3 and Runx1 in the niche that supports embryonic HSCs and highlight a dual role for Runx1 in driving the transdifferentiation of haemogenic endothelial cells into HSCs as well as in the stromal cells that support this process.
Gonads, Aorta, Endothelium, Vascular, Hematopoietic Stem Cells, Mesonephros, Animals, Mice, Inbred C57BL, Mice, Hematopoiesis, Embryonic Development, Female, Core Binding Factor Alpha 2 Subunit, GATA3 Transcription Factor, Embryo, Mammalian
This work was supported by an Intermediate Fellowship (K.O.) and a Junior Fellowship (S.R.F.) from the Kay Kendall Leukaemia Fund, a British Society for Haematology Early Stage Investigator Fellowship (K.O.) as well as funding from Bloodwise (N.K.W. and B.G.), MRC (N.K.W. and B.G.) and the Wellcome Trust (N.K.W. and B.G.). MdB is funded by a programme in the MRC Molecular Hematology Unit Core award (Grant number: MC_UU_12009/2). Core facilities are supported by Strategic Award WT100140, equipment grant 093026 and centre grant MR/K017047/1.
Wellcome Trust (206328/Z/17/Z)
Wellcome Trust (079895/Z/06/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (093026/Z/10/Z)
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External DOI: https://doi.org/10.1002/iub.2184
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297924
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/