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Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development
Open accessAbstract
Conservation of the vertebrate body plan has been attributed to the evolutionary stability of gene-regulatory networks (GRNs). We describe a regulatory circuit made up of Gata2, Fli1, and Scl/Tal1 and their enhancers, Gata2-3 , Fli1 +12, and Scl +19, that operates during specification of hematopoiesis in the mouse embryo. We show that the Fli1 +12 enhancer, like the Gata2-3 and Scl +19 enhancers, targets hematopoietic stem cells (HSCs) and relies on a combination of Ets, Gata, and E-Box motifs. We show that the Gata2-3 enhancer also uses a similar cluster of motifs and that Gata2, Fli1, and Scl are expressed in embryonic day-11.5 dorsal aorta where HSCs originate and in fetal liver where they multiply. The three HSC enhancers in these tissues and in ES cell-derived hemangioblast equivalents are bound by each of these transcription factors (TFs) and form a fully connected triad that constitutes a previously undescribed example of both this network motif in mammalian development and a GRN kernel operating during the specification of a mammalian stem cell.
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“A recursively wired triple feedback circuit has been proposed as a kernel underlying the pluripotential state of endothelial/hematopoietic precursors that arise in vertebrate development (Pimanda et al., 2007).”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Pimanda et al., 2007
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“This sub-circuit consists of three positively active genes. There are no cross-regulating repressors in this sub-circuit, and the three genes are linked by multiple positive auto- and cross-regulatory linkages.”
From Emerging properties of animal gene regulatory networks (2010) · cites this paper as [28]
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Metadata
- Authors
- Pimanda, J. E., Ottersbach, K., Knezevic, K., Kinston, S., Chan, W. Y. I., Wilson, N. K., Landry, J.-R., Wood, A. D., Kolb-Kokocinski, A., Green, A. R., Tannahill, D., Lacaud, G., Kouskoff, V., & Göttgens, B.
- Affiliations
- University of Cambridge (GB)
- The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom; and
- Wellcome Sanger Institute (GB)
- Cancer Research UK Manchester Institute (GB)
- Paterson Institute for Cancer Research, Manchester M20 4BX, United Kingdom
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-11-06
- Volume
- 104
- Issue
- 45
- Pages
- 17692-17697
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2077040
- OpenAlex
- W1996351707
- Cited by
- 228
- References
- 46
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 11 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 9 · 2017: 8 · 2016: 19 · 2015: 16 · 2014: 17 · 2013: 22 · 2012: 18
- FWCI
- 10.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Wellcome Trust
- Kay Kendall Leukaemia Fund
- University of Oxford
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- GATA2, FLI1, SCL/TAL1, gene regulatory networks, hematopoietic stem cells, enhancers, transcription factor binding motifs, E-box motifs, dorsal aorta, fetal liver, hemangioblasts, embryonic stem cells, hematopoietic specification, network motifs
- MeSH terms
- T-Cell Acute Lymphocytic Leukemia Protein 1, Animals, Binding Sites, Blood Vessels, Embryo, Mammalian, Enhancer Elements, Genetic, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Proto-Oncogene Proteins, GATA2 Transcription Factor, Mice, Proto-Oncogene Protein c-fli-1, Basic Helix-Loop-Helix Proteins
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