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Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases

Author

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  • Carlos Moreno-Yruela

    (University of Copenhagen)

  • Michael Bæk

    (University of Copenhagen)

  • Adela-Eugenie Vrsanova

    (University of Copenhagen
    Karlsruhe Institute of Technology
    DKFZ German Cancer Research Center)

  • Clemens Schulte

    (University of Würzburg)

  • Hans M. Maric

    (University of Würzburg)

  • Christian A. Olsen

    (University of Copenhagen)

Abstract

Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the epigenetic landscape, which is tightly controlled by epigenetic modulator enzymes and further recognized by so-called reader domains. Histone microarrays have been widely applied to investigate histone–reader interactions, but not the transient interactions of Zn2+-dependent histone deacetylase (HDAC) eraser enzymes. Here, we synthesize hydroxamic acid-modified histone peptides and use them in femtomolar microarrays for the direct capture and detection of the four class I HDAC isozymes. Follow-up functional assays in solution provide insights into their suitability to discover HDAC substrates and inhibitors with nanomolar potency and activity in cellular assays. We conclude that similar hydroxamic acid-modified histone peptide microarrays and libraries could find broad application to identify class I HDAC isozyme-specific substrates and facilitate the development of isozyme-selective HDAC inhibitors and probes.

Suggested Citation

  • Carlos Moreno-Yruela & Michael Bæk & Adela-Eugenie Vrsanova & Clemens Schulte & Hans M. Maric & Christian A. Olsen, 2021. "Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20250-9
    DOI: 10.1038/s41467-020-20250-9
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