title: EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2.
abstract: Differentiation of erythroid cells requires precise control over the cell cycle to regulate the balance between cell proliferation and differentiation. The zinc finger transcription factor, erythroid Krüppel-like factor (EKLF/KLF1), is essential for proper erythroid cell differentiation and regulates many erythroid genes. Here we show that loss of EKLF leads to aberrant entry into S-phase of the cell cycle during both primitive and definitive erythropoiesis. This cell cycle defect was associated with a significant reduction in the expression levels of E2f2 and E2f4, key factors necessary for the induction of S-phase gene expression and erythropoiesis. We found and validated novel intronic enhancers in both the E2f2 and E2f4 genes, which contain conserved CACC, GATA, and E-BOX elements. The E2f2 enhancer was occupied by EKLF in vivo. Furthermore, we were able to partially restore cell cycle dynamics in EKLF(-/-) fetal liver upon additional genetic depletion of Rb, establishing a genetic causal link between reduced E2f2 and the EKLF cell cycle defect. Finally, we propose direct regulation of the E2f2 enhancer is a generic mechanism by which many KLFs regulate proliferation and differentiation.
authors.affiliation: Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, 4072, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tallack
authors.forename: Janelle R
authors.initials: JR
authors.lastname: Keys
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Humbert
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Perkins
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle; D017124:Conserved Sequence; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism*; D004920:Erythropoiesis; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007438:Introns / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050703:E2F2 Transcription Factor; D050704:E2F4 Transcription Factor; C484940:E2f2 protein, mouse; C493763:E2f4 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor