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The use of short epitope tags is widespread in the study of histone H3 biology as they allow for the antibody-mediated detection and pulldown of particular histone post-translational modifications (PTM) or exogenous histone transgenes. However, H3 is particularly sensitive to sequence modification and the addition of epitope tags may interfere with the native function of H3. Here, we use the known relationship between lysine-to-methionine K27M mutations and the loss of trimethylation at the H3 K27 residue to test whether the addition of epitope tags to the N or C terminus of H3 affects the levels of histone H3 PTMs. We find that all tested N-terminal tags abrogate the H3K27M-mediated loss of H3K27 trimethylation. These results suggest that the addition of epitope tags to the N-terminus of H3 should be performed with caution, and these findings may be of particular interest for the study of H3-driven cancers, like diffuse midline gliomas.