title: Tissue-specific targeting of cell fate regulatory genes by E2f factors.
abstract: Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-β signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell type-specific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.
authors.affiliation: Neuroscience program, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: L M
authors.initials: LM
authors.lastname: Julian
authors.affiliation: Department of Biochemsitry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Neuroscience program, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: C A
authors.initials: CA
authors.lastname: Pakenham
authors.affiliation: Neuroscience program, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Dugal-Tessier
authors.affiliation: Neuroscience program, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Ruzhynsky
authors.affiliation: Solid Tumor Biology Program, Department of Molecular Virology, Immunology, and Medical Genetics and Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bae
authors.affiliation: Solid Tumor Biology Program, Department of Molecular Virology, Immunology, and Medical Genetics and Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Solid Tumor Biology Program, Department of Molecular Virology, Immunology, and Medical Genetics and Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: G
authors.initials: G
authors.lastname: Leone
authors.affiliation: Neuroscience program, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: R S
authors.initials: RS
authors.lastname: Slack
authors.affiliation: Department of Biochemsitry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Blais
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000076246:CCCTC-Binding Factor; C000619698:Ctcf protein, mouse; D050684:E2F Transcription Factors; D012097:Repressor Proteins