Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2.

Abstract

Erythroid Krüppel-like factor (EKLF) is a Krüppel-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.

• Authors: Andre M Pilon, Murat O Arcasoy, Holly K Dressman, Serena E Vayda, Yelena D Maksimova, Jose I Sangerman, Patrick G Gallagher, David M Bodine
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 28 Issue 24 Pg. 7394-401 (Dec 2008) ISSN: 1098-5549 [Electronic] United States
• PMID: 18852285 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• E2F2 Transcription Factor
• Kruppel-Like Transcription Factors
• erythroid Kruppel-like factor

Topics

• Animals
• Cell Cycle (physiology)
• Cell Differentiation (physiology)
• E2F2 Transcription Factor (genetics, metabolism)
• Embryo, Mammalian (anatomy & histology, physiology)
• Erythropoiesis (physiology)
• Gene Expression Profiling
• Gene Expression Regulation, Developmental
• Gene Regulatory Networks
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Liver (cytology, embryology)
• Mice
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic
• Stem Cells (cytology, physiology)
• Transcription, Genetic