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4 results on '"Chan, Wan Y.I."'

2. Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development

Author

Pimanda, John E., Ottersbach, Katrin, Knezevic, Kathy, Kinston, Sarah, Chan, Wan Y.I., Wilson, Nicola K., Landry, Josette-Renee, Wood, Andrew D., Kolb-Kokocinski, Anja, Green, Anthony R., Tannahill, David, Lacaud, Georges, Kouskoff, Valerie, and Gottgens, Berthold

Subjects
Hematopoietic system -- Genetic aspects, Hematopoietic stem cells -- Properties, DNA binding proteins -- Properties, Science and technology
Abstract

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 Sci+19, that operates during specification of hematopoiesis in the mouse embryo. We show that the Fli1+12 enhancer, like the Gata2-3 and Sci + 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. hemangioblast | hematopoiesis | hematopoietic stem cell | network motif | transcription factor network

Published
2007

4. The paralogous hematopoietic regulators Lyl1and Sclare coregulated by Ets and GATA factors, but Lyl1cannot rescue the early Scl–/–phenotype

Author

Chan, Wan Y.I., Follows, George A., Lacaud, Georges, Pimanda, John E., Landry, Josette-Renee, Kinston, Sarah, Knezevic, Kathy, Piltz, Sandie, Donaldson, Ian J., Gambardella, Laure, Sablitzky, Fred, Green, Anthony R., Kouskoff, Valerie, and Göttgens, Berthold

Abstract

Transcription factors are key regulators of hematopoietic stem cells (HSCs), yet the molecular mechanisms that control their expression are largely unknown. Previously, we demonstrated that expression of Scl/Tal1, a transcription factor required for the specification of HSCs, is controlled by Ets and GATA factors. Here we characterize the molecular mechanisms controlling expression of Lyl1, a paralog of Sclalso required for HSC function. Two closely spaced promoters directed expression to hematopoietic progenitor, megakaryocytic, and endothelial cells in transgenic mice. Conserved binding sites required for promoter activity were bound in vivo by GATA-2 and the Ets factors Fli1, Elf1, Erg, and PU.1. However, despite coregulation of Scland Lyl1by the same Ets and GATA factors, Sclexpression was initiated prior to Lyl1in embryonic stem (ES) cell differentiation assays. Moreover, ectopic expression of Sclbut not Lyl1rescued hematopoietic differentiation in Scl−/−ES cells, thus providing a molecular explanation for the vastly different phenotypes of Scl−/−and Lyl1−/−mouse embryos. Furthermore, coregulation of Scland Lyl1later during development may explain the mild phenotype of Scl−/−adult HSCs.

Published
2007
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