Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment.
The hierarchical progression of stem and progenitor cells to their more-committed progeny is mediated through cell-to-cell signaling pathways and intracellular transcription factor activity. However, the mechanisms that govern the genetic networks underlying lineage fate decisions and differentiation programs remain poorly understood. Here we show how integration of Bmp4 signaling and Gata factor activity controls the progression of hematopoiesis, as exemplified by the regulation of Eklf during establishment of the erythroid lineage. Utilizing transgenic reporter assays in differentiating mouse embryonic stem cells as well as in the murine fetal liver, we demonstrate that Eklf expression is initiated prior to erythroid commitment during hematopoiesis. Applying phylogenetic footprinting and in vivo binding studies in combination with newly developed loss-of-function technology in embryoid bodies, we find that Gata2 and Smad5 cooperate to induce Eklf in a progenitor population, followed by a switch to Gata1-controlled regulation of Eklf transcription upon erythroid commitment. This stage- and lineage-dependent control of Eklf expression defines a novel role for Eklf as a regulator of lineage fate decisions during hematopoiesis.
Lohmann
Felix
F
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, Box 1020, 1 Gustave Levy Place, New York, NY 10029, USA.
Bieker
James J
JJ
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000502:physiology*; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006410:Hematopoiesis; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010802:Phylogeny; D012689:Sequence Homology, Nucleic Acid; D051902:Smad5 Protein / Q000235:genetics / Q000502:physiology*
D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; C080774:erythroid Kruppel-like factor