Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development.
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.
Pimanda
John E
JE
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom. jpimanda@unsw.edu.au
Ottersbach
Katrin
K
Knezevic
Kathy
K
Kinston
Sarah
S
Chan
Wan Y I
WY
Wilson
Nicola K
NK
Landry
Josette-Renée
JR
Wood
Andrew D
AD
Kolb-Kokocinski
Anja
A
Green
Anthony R
AR
Tannahill
David
D
Lacaud
Georges
G
Kouskoff
Valerie
V
Göttgens
Berthold
B
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001808:Blood Vessels / Q000196:embryology / Q000502:physiology; D004622:Embryo, Mammalian / Q000502:physiology; D004742:Enhancer Elements, Genetic; D050989:GATA2 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D051789:Proto-Oncogene Protein c-fli-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D050989:GATA2 Transcription Factor; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C497426:Fli1 protein, mouse; C494712:Gata2 protein, mouse; C489366:Tal1 protein, mouse