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Background  The dynamics of histone post-translational modifications (PTMs) are sparsely described, especially in their true physiological context of proteoforms (single histone molecules harboring combinations of PTMs).    Methods  Here we time-resolve the response of cells to SUV4-20 methyltransferase inhibition and unbiasedly quantitate the dynamic response of histone H4 PTMs and proteoforms.    Results  Contrary to the prevailing dogma, cells exhibit an immediate-early response with changes to histone proteoforms. Cells also recover to basal-like conditions upon removal of epigenetic inhibitors rapidly. Inhibition of SUV4-20 results in decreased H4{K20me2}; however, no effects on H4{K20me3} are observed, implying that another enzyme mediates H4K20me3. Most surprisingly, SUV4-20 inhibition results in an increase in histone H4 acetylation attributable to proteoforms containing K20me2. This led us to hypothesize that hyperacetylated proteoforms protect K20me2 from demethylation as an evolved compensatory mechanism. This concept is supported by subsequent results that pretreatment with an HDACi substantially diminishes the effects of SUV4-20 inhibition in prone cells and is further confirmed by HATi-facilitating SUV4-20 inhibition to decrease discrete H4{K20me2} in resistant cells.    Conclusions  The chromatin response of cells to sudden perturbations is significantly faster, nuanced and complex than previously described. The persistent nature of chromatin regulation may be achieved by a network of dynamic equilibria with compensatory mechanisms that operate at the proteoform level.    Electronic supplementary material  The online version of this article (10.1186/s13072-018-0198-9) contains supplementary material, which is available to authorized users.

The histone H4 proteoform dynamics in response to SUV4-20 inhibition reveals single molecule mechanisms of inhibitor resistance