Specification of hematopoietic and vascular development by the bHLH transcription factor SCL without direct DNA binding.
Transcription factors, such as those of the basic-helix-loop-helix (bHLH) and homeodomain classes, are primary regulators of cell fate decisions and differentiation. It is considered axiomatic that they control their respective developmental programs via direct binding to cognate DNA sequences in critical targets genes. Here we test this widely held paradigm by in vivo functional assay of the leukemia oncoprotein SCL, a bHLH factor that resembles myogenic and neurogenic proteins and is essential for both hematopoietic and vascular development in vertebrates. Contrary to all expectation, we find that SCL variants unable to bind DNA rescue hematopoiesis from gene-targeted SCL(-)(/)(-) embryonic stem cells and complement hematopoietic and vascular deficits in the zebrafish mutant cloche. Our findings establish DNA-binding-independent functions of SCL critical for transcriptional specification, and should encourage reassessment of presumed requirements for direct DNA binding by other transcription factors during initiation of developmental programs.
Porcher
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Division of Hematology and Oncology, Children's Hospital and Dana Farber Cancer Institute, Department of Pediatrics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
Liao
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EC
Fujiwara
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Y
Zon
L I
LI
Orkin
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SH
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D001808:Blood Vessels / Q000196:embryology*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D018257:Helix-Loop-Helix Motifs / Q000235:genetics / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D007938:Leukemia / Q000209:etiology / Q000235:genetics; D009154:Mutation; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; D029961:Zebrafish Proteins; C489367:tal1 protein, zebrafish; C067143:TAL1 protein, human