title: Genome-wide identification of cis-regulatory sequences controlling blood and endothelial development.
abstract: The development of blood has long served as a model for mammalian cell type specification and differentiation, and yet the underlying transcriptional networks remain ill defined. Characterization of such networks will require genome-wide identification of cis-regulatory sequences and an understanding of how regulatory information is encoded in the primary DNA sequence. Despite progress in lower organisms, genome-wide computational identification of mammalian cis-regulatory sequences has been hindered by increased genomic complexity and cumbersome transgenic assays. Starting with a well-characterized blood stem cell enhancer from the SCL gene, we have developed computational tools for the identification of functionally related gene regulatory sequences. Two candidate enhancers discovered in this way were located in intron 1 of the Fli-1 and PRH/Hex genes, both transcription factors previously implicated in controlling blood and endothelial development. Subsequent transgenic and biochemical analysis demonstrated that the two computationally identified enhancers are functionally related to the SCL stem cell enhancer. The approach developed here may therefore be useful for identifying additional enhancers involved in the control of early blood and endothelial development, and may be adapted to decipher transcriptional regulatory codes controlling a broad range of mammalian developmental programmes.
authors.affiliation: Department of Haematology, Cambridge Institue for Medical Research, Cambridge University, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Donaldson
authors.forename: Michael
authors.initials: M
authors.lastname: Chapman
authors.forename: Sarah
authors.initials: S
authors.lastname: Kinston
authors.forename: Josette Renée
authors.initials: JR
authors.lastname: Landry
authors.forename: Kathy
authors.initials: K
authors.lastname: Knezevic
authors.forename: Sandie
authors.initials: S
authors.lastname: Piltz
authors.forename: Noel
authors.initials: N
authors.lastname: Buckley
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012984:Software; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors