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Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting

Lauren A Solomon1,2, Shreya Podder1,2, Jessica He1,2

  • 1Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Molecular and Cellular Biology
|February 23, 2017
PubMed

Insights

Transcription factor PU.1 coordinates macrophage differentiation with cell cycle reduction by inducing microRNAs. These microRNAs target genes involved in cell cycle progression and lipid metabolism, linking PU.1 to myeloid cell development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Macrophage development involves terminal differentiation and reduced cell cycle progression.
  • The transcription factor PU.1 is crucial for macrophage differentiation, with reduced expression impairing this process and increasing proliferation.
  • The mechanism by which PU.1 coordinates differentiation with cell cycle regulation remains unclear.

Purpose of the Study:

  • To identify PU.1 targets involved in regulating cell cycle progression during macrophage differentiation.
  • To elucidate how PU.1 influences cell cycle regulators and lipid metabolism.
  • To investigate the role of microRNAs in mediating PU.1's effects on cell cycle and differentiation.

Main Methods:

  • Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) in PU.1-inducible myeloid cells.
  • Gene expression analysis to identify PU.1 targets.
  • Next-generation sequencing to identify microRNAs.
  • Validation of microRNA targets involved in cell cycle and lipid metabolism.

Main Results:

  • PU.1 directly binds to genes regulating cell cycle and lipid anabolism, leading to reduced mRNA levels.
  • Inhibition of lipid anabolism effectively reduces cell cycle progression.
  • PU.1 induces microRNA 223, which indirectly downregulates E2f1, a key regulator of cell cycle and lipid metabolism.
  • MicroRNAs targeting cell cycle and lipid anabolism were identified and validated.

Conclusions:

  • PU.1 coordinates macrophage differentiation with cell cycle progression.
  • This coordination is achieved through the induction of microRNAs that target cell cycle regulators and lipid anabolism pathways.
  • PU.1's regulatory network involves microRNAs in controlling myeloid progenitor cell fate and proliferation.
Keywords:
E2F1PU.1cell cycledifferentiationlipid synthesismicroRNAmyeloid cells

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