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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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Deubiquitinating enzymes regulate Hes1 stability and neuronal differentiation.

Taeko Kobayashi1,2,3,4, Yumiko Iwamoto1, Kazuhiro Takashima1

  • 1Institute for Virus Research, Kyoto University, Japan.

The FEBS Journal
|April 8, 2015
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Summary

Deubiquitinases like Usp27x stabilize the Hes1 protein, a key regulator of neural stem cell maintenance. This regulation impacts Hes1 oscillations and controls neuronal differentiation during brain development.

Keywords:
Hes1basic helix-loop-helix transcription factor (bHLH)deubiquitinationneurodevelopmentoscillation

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Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Stem Cell Biology

Background:

  • Hairy and enhancer of split 1 (Hes1) is a transcriptional repressor crucial for neural stem/progenitor cell maintenance via Notch signaling.
  • Hes1 expression oscillates, influencing stem cell potency and differentiation, with stability regulated by the ubiquitin/proteasome pathway.

Purpose of the Study:

  • To identify molecular mechanisms governing Hes1 protein stability.
  • To investigate the role of deubiquitinases in regulating Hes1 dynamics and neuronal differentiation.

Main Methods:

  • Co-immunoprecipitation of Hes1-interacting proteins from mouse embryonic stem cells.
  • Identification of deubiquitinases interacting with Hes1.
  • Analysis of Hes1 half-life, oscillation, and neuronal differentiation following manipulation of deubiquitinase expression (knockdown/mis-expression).

Main Results:

  • Ubiquitin-specific protease 27x (Usp27x) and its homologs Usp22 and Usp51 were identified as Hes1-interacting deubiquitinases.
  • Usp27x, Usp22, and Usp51 deubiquitinate and stabilize Hes1.
  • Usp22 knockdown reduced Hes1 half-life, delayed oscillations, and promoted neuronal differentiation.
  • Usp27x mis-expression inhibited neuronal differentiation.

Conclusions:

  • Deubiquitinases modulate Hes1 protein stability by removing ubiquitin tags.
  • This regulation of Hes1 dynamics by deubiquitinases is critical for controlling neuronal differentiation in developing brains.