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Related Experiment Videos

Human histone demethylase LSD1 reads the histone code.

Federico Forneris1, Claudia Binda, Maria Antonietta Vanoni

  • 1Dipartimento di Genetica e Microbiologia, Università di Pavia, Via Ferrata 1, Pavia 27100, Italy.

The Journal of Biological Chemistry
|October 15, 2005
PubMed
Summary

Histone demethylase LSD1 activity is modulated by histone modifications. Lysine 9 acetylation and serine 10 phosphorylation significantly impact LSD1

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Area of Science:

  • Biochemistry and Molecular Biology
  • Epigenetics
  • Enzymology

Background:

  • Histone demethylase Lysine Specific Demethylase 1 (LSD1) removes methyl groups from histone H3 at Lysine 4 (K4).
  • The N-terminal tail of histone H3 is subject to various post-translational modifications.
  • Understanding how these modifications influence LSD1 activity is crucial for comprehending epigenetic regulation.

Purpose of the Study:

  • To investigate the substrate specificity of human LSD1 regarding Lys4 methylation states.
  • To determine the impact of additional histone modifications on Lys4 demethylation by LSD1.
  • To elucidate the role of electrostatic interactions in LSD1-substrate recognition.

Main Methods:

  • Enzyme kinetics assays were performed using varying peptide substrates representing histone H3 N-terminal tails.

Related Experiment Videos

  • Kinetic parameters (Km) were measured under different ionic strengths to assess electrostatic contributions.
  • The effect of Lysine 9 methylation, acetylation, and Serine 10 phosphorylation on LSD1 activity was evaluated.

    • Main Results:

    • LSD1 exhibits no strong preference between mono- and dimethylated Lys4.
    • Substrate recognition requires a peptide segment of at least the N-terminal 20 amino acids of H3.
    • Lysine 9 methylation has no effect, Lysine 9 acetylation increases Km by ~6-fold, and Serine 10 phosphorylation abolishes activity.
    • LSD1 binds to H3 independently of Lys4 methylation, with inhibition by demethylated peptide (Ki = 1.8 µM).

    Conclusions:

    • LSD1's activity is sensitive to specific epigenetic marks on the histone H3 tail, particularly Ser10 phosphorylation and K9 acetylation.
    • LSD1 can recognize and bind to histone H3 independent of Lys4 methylation status.
    • LSD1 functions as a chromatin-modifying enzyme capable of integrating multiple epigenetic signals for gene regulation.