title: Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism.
abstract: During macrophage development, myeloid progenitor cells undergo terminal differentiation coordinated with reduced cell cycle progression. Differentiation of macrophages from myeloid progenitors is accompanied by increased expression of the E26 transformation-specific transcription factor PU.1. Reduced PU.1 expression leads to increased proliferation and impaired differentiation of myeloid progenitor cells. It is not understood how PU.1 coordinates macrophage differentiation with reduced cell cycle progression. In this study, we utilized cultured PU.1-inducible myeloid cells to perform genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis coupled with gene expression analysis to determine targets of PU.1 that may be involved in regulating cell cycle progression. We found that genes encoding cell cycle regulators and enzymes involved in lipid anabolism were directly and inducibly bound by PU.1 although their steady-state mRNA transcript levels were reduced. Inhibition of lipid anabolism was sufficient to reduce cell cycle progression in these cells. Induction of PU.1 reduced expression ofE2f1, an important activator of genes involved in cell cycle and lipid anabolism, indirectly through microRNA 223. Next-generation sequencing identified microRNAs validated as targeting cell cycle and lipid anabolism for downregulation. These results suggest that PU.1 coordinates cell cycle progression with differentiation through induction of microRNAs targeting cell cycle regulators and lipid anabolism.
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Solomon
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Shreya
authors.initials: S
authors.lastname: Podder
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Jackson-Chornenki
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Kristen
authors.initials: K
authors.lastname: Gibson
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Ziliotto
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Jess
authors.initials: J
authors.lastname: Rhee
authors.affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada rdekoter@uwo.ca.|Centre for Human Immunology, Western University, London, Ontario, Canada.|Division of Genetics and Development, Children's Health Research Institute, Lawson Research Institute, London, Ontario, Canada.
authors.forename: Rodney P
authors.identifier: http://orcid.org/0000-0002-9201-1983
authors.initials: RP
authors.lastname: DeKoter
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D035683:MicroRNAs; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D001275:ATP Citrate (pro-S)-Lyase; D050687:E2F1 Transcription Factor; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
keywords: E2F1; PU.1; cell cycle; differentiation; lipid synthesis; microRNA; myeloid cells