title: A global role for EKLF in definitive and primitive erythropoiesis.
abstract: Erythroid Kruppel-like factor (EKLF, KLF1) plays an important role in definitive erythropoiesis and beta-globin gene regulation but failure to rectify lethal fetal anemia upon correction of globin chain imbalance suggested additional critical EKLF target genes. We employed expression profiling of EKLF-null fetal liver and EKLF-null erythroid cell lines containing an inducible EKLF-estrogen receptor (EKLF-ER) fusion construct to search for such targets. An overlapping list of EKLF-regulated genes from the 2 systems included alpha-hemoglobin stabilizing protein (AHSP), cytoskeletal proteins, hemesynthesis enzymes, transcription factors, and blood group antigens. One EKLF target gene, dematin, which encodes an erythrocyte cytoskeletal protein (band 4.9), contains several phylogenetically conserved consensus CACC motifs predicted to bind EKLF. Chromatin immunoprecipitation demonstrated in vivo EKLF occupancy at these sites and promoter reporter assays showed that EKLF activates gene transcription through these DNA elements. Furthermore, investigation of EKLF target genes in the yolk sac led to the discovery of unexpected additional defects in the embryonic red cell membrane and cytoskeleton. In short, EKLF regulates global erythroid gene expression that is critical for the development of primitive and definitive red cells.
authors.affiliation: Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Hodge
authors.forename: Elise
authors.initials: E
authors.lastname: Coghill
authors.forename: Janelle
authors.initials: J
authors.lastname: Keys
authors.forename: Tina
authors.initials: T
authors.lastname: Maguire
authors.forename: Belinda
authors.initials: B
authors.lastname: Hartmann
authors.forename: Alasdair
authors.initials: A
authors.lastname: McDowall
authors.forename: Mitchell
authors.initials: M
authors.lastname: Weiss
authors.forename: Sean
authors.initials: S
authors.lastname: Grimmond
authors.forename: Andrew
authors.initials: A
authors.lastname: Perkins
mesh_terms: D000740:Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004910:Erythrocyte Membrane / Q000235:genetics / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005804:Genes, Lethal / Q000235:genetics; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D015017:Yolk Sac / Q000196:embryology / Q000473:pathology
chemical_list: D002843:Chromatin; D051741:Kruppel-Like Transcription Factors; C080774:erythroid Kruppel-like factor; D005914:Globins