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Failure of Terminal Erythroid Differentiation in EKLF-Deficient Mice Is Associated with Cell Cycle Perturbation and Reduced Expression of E2F2

2008; Taylor & Francis; Volume: 28; Issue: 24 Linguagem: Inglês

10.1128/mcb.01087-08

1098-5549

André M. Pilon, Murat O. Arcasoy, Holly K. Dressman, Serena E. Vayda, Yelena Maksimova, José Sangerman, Patrick G. Gallagher, David M. Bodine,

RNA modifications and cancer

Erythroid Kru ¨ppel-like factor (EKLF) is a Kru ¨ppel-like transcription factor identified as a transcriptional activator and chromatin modifier in erythroid cells.EKLF-deficient (Eklf ؊/؊ ) mice die at day 14.5 of gestation from severe anemia.In this study, we demonstrate that early progenitor cells fail to undergo terminal erythroid differentiation in Eklf ؊/؊ embryos.To discover potential EKLF target genes responsible for the failure of erythropoiesis, transcriptional profiling was performed with RNA from wild-type and Eklf ؊/؊ early erythroid progenitor cells.These analyses identified significant perturbation of a network of genes involved in cell cycle regulation, with the critical regulator of the cell cycle, E2f2, at a hub.E2f2 mRNA and protein levels were markedly decreased in Eklf ؊/؊ early erythroid progenitor cells, which showed a delay in the G 1 -to-S-phase transition.Chromatin immunoprecipitation analysis demonstrated EKLF occupancy at the proximal E2f2 promoter in vivo.Consistent with the role of EKLF as a chromatin modifier, EKLF binding sites in the E2f2 promoter were located in a region of EKLF-dependent DNase I sensitivity in early erythroid progenitor cells.We propose a model in which EKLF-dependent activation and modification of the E2f2 locus is required for cell cycle progression preceding terminal erythroid differentiation.