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Epigenetics

Epigenetic discovery by enzyme activity profiling

Nature Reviews Molecular Cell Biology volume 26, page 83 (2025)Cite this article

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In the mid-1990s, the field of histone acetylation was ripe with questions. Although the correlation between histone acetylation and gene activation had been established, the mechanisms responsible for this modification remained unclear. The existence of specific histone acetyltransferases (HATs) was hypothesized but unproven, and the precise role of acetylation in gene regulation was not known. It was in this context that the choice of C. David Allis to study Tetrahymena, a ciliate protozoan, proved to be a stroke of brilliance. This single-celled organism, with its unique dual nuclei and abundance of transcriptionally active chromatin, offered an ideal model for isolating HAT activity. What might have seemed an esoteric choice at first, turned out to be the key to unlocking fundamental principles of epigenetic regulation. It is a reminder that nature’s laboratory is vast and varied, and that sometimes the most profound insights come from the most unexpected sources.

Allis’s work also resonates from a chemical biology perspective, as it highlights the enduring value of activity-guided fractionation. Brownell et al. isolated the first HAT enzyme using a novel activity assay, which tracked the transfer of radiolabelled acetyl-CoA to a histone-impregnated polyacrylamide gel. Although it may seem old-fashioned, this principle lives on in contemporary techniques such as activity-based protein profiling (ABPP), which was invented concurrently with the discovery of HATs and used to study enzyme activities such as the proteasome and fatty acid amide hydrolase. Similar to traditional fractionation, ABPP allows us to focus on proteins with functionally relevant properties, such as enzyme activity or a new druggable pocket, amid the cellular milieu. Fittingly, drug developers now rely on ABPP to validate the protein targets of small molecules, including cancer treatments that target histone acetylation. Our goals and methods continually evolve, but we still rely on the fundamental principle of following biological activity to its source.

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References

Original articles

  • Brownell, J. E. & Allis, C. D. An activity gel assay detects a single, catalytically active histone acetyltransferase subunit in Tetrahymena macronuclei. Proc. Natl Acad. Sci. USA 92, 6364–6368 (1995)

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Related article

  • Bogyo, M., Shin, S., McMaster, J. S. & Ploegh, H. L. Substrate binding and sequence preference of the proteasome revealed by active-site-directed affinity probes. Chem. Biol. 5, 307–320 (1998)

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  1. Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA

    Manini S. Penikalapati & Jordan L. Meier

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  1. Manini S. Penikalapati
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  2. Jordan L. Meier
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Correspondence to Jordan L. Meier.

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The authors declare no competing interests.

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Penikalapati, M.S., Meier, J.L. Epigenetic discovery by enzyme activity profiling. Nat Rev Mol Cell Biol 26, 83 (2025). https://doi.org/10.1038/s41580-024-00801-4

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