Coordination of myeloid differentiation with reduced cell cycle progression by PU.1 induction of MicroRNAs targeting cell cycle regulators and lipid anabolism
Open accessAbstract
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 of E2f1, 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.
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PU.1 binds to and represses key genes in glycolysis and lipid biosynthesis pathways used for production of energy and anabolic factors that support cell proliferation.
“These observations are broadly consistent with prior work showing that PU.1 binds to and represses key genes in glycolysis and lipid biosynthesis pathways used for production of energy and anabolic factors that support cell proliferation (Solomon et al., 2017).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Solomon et al., 2017
The Results and Discussion (page numbers unavailable) report that PU.1 binding is associated with reduced expression of lipid-anabolism genes and reduced cell-cycle progression. They do not establish repression of glycolysis genes. The Discussion also distinguishes binding from direct transcriptional repression: it suggests that PU.1 activates some bound genes transcriptionally while induced microRNAs reduce their steady-state expression. (LLM, conf=0.90)
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- Authors
- Solomon, L. A., Podder, S., He, J., Jackson-Chornenki, N. L., Gibson, K., Ziliotto, R. G., Rhee, J., & DeKoter, R. P.
- Affiliations
- Western University (CA)
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2017-05-01
- Volume
- 37
- Issue
- 10
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC5477546
- OpenAlex
- W2590807328
- Cited by
- 22
- References
- 49
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 1
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- Funders
- Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (386046-2010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- PU.1, myeloid differentiation, macrophage development, cell cycle progression, microRNA, miR-223, E2F1, cell cycle regulators, transcriptional regulation, myeloid progenitor cells, chromatin binding
- MeSH terms
- Proto-Oncogene Protein Spi-1, ATP Citrate (pro-S)-Lyase, Cell Cycle, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Humans, Macrophages, Proto-Oncogene Proteins, Trans-Activators, Myeloid Cells, MicroRNAs, Lipid Metabolism, E2F1 Transcription Factor
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