EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2.
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.
Tallack
Michael R
MR
Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, 4072, Australia.
Keys
Janelle R
JR
Humbert
Patrick O
PO
Perkins
Andrew C
AC
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
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