Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors.
Stem cells are a central feature of metazoan biology. Haematopoietic stem cells (HSCs) represent the best-characterized example of this phenomenon, but the molecular mechanisms responsible for their formation remain obscure. The stem cell leukaemia (SCL) gene encodes a basic helix-loop-helix (bHLH) transcription factor with an essential role in specifying HSCs. Here we have addressed the transcriptional hierarchy responsible for HSC formation by characterizing an SCL 3' enhancer that targets expression to HSCs and endothelium and their bipotential precursors, the haemangioblast. We have identified three critical motifs, which are essential for enhancer function and bind GATA-2, Fli-1 and Elf-1 in vivo. Our results suggest that these transcription factors are key components of an enhanceosome responsible for activating SCL transcription and establishing the transcriptional programme required for HSC formation.
Göttgens
Berthold
B
University of Cambridge Department of Haematology, Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 2XY, UK. bg200@cam.ac.uk
Nastos
Aristotelis
A
Kinston
Sarah
S
Piltz
Sandie
S
Delabesse
Eric C M
EC
Stanley
Maureen
M
Sanchez
Maria-Jose
MJ
Ciau-Uitz
Aldo
A
Patient
Roger
R
Green
Anthony R
AR
D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000502:physiology; D004625:Embryo, Nonmammalian; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D050989:GATA2 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D018257:Helix-Loop-Helix Motifs / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D011485:Protein Binding; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016415:Sequence Alignment; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D029867:Xenopus Proteins; C497426:Fli1 protein, mouse; C494714:GATA2 protein, Xenopus; C494711:GATA2 protein, human; C494712:Gata2 protein, mouse; C489365:TAL1 protein, Xenopus; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human