Abstract
BackgroundThe 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).MethodsHere we time-resolve the response of cells to SUV4-20 methyltransferase inhibition and unbiasedly quantitate the dynamic response of histone H4 PTMs and proteoforms.ResultsContrary 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.ConclusionsThe 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.
Highlights
The dynamics of histone post-translational modifications (PTMs) are sparsely described, especially in their true physiological context of proteoforms
We find that K20me2 is regulated in an unprecedentedly dynamic and remarkably nuanced way, while SUV4-20 is not associated with K20me3
A relatively extensive set of histone H4 PTMs are characterized in this study (Fig. 1a, b)
Summary
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). The recruitment of regulatory proteins is widely accepted as the primary role of histone PTMs. The current evidence suggests that there is a moderately strong, but not strictly injective (one-to-one) relationship between discrete histone PTMs and specific biological function [4, 5]. Considering that H4K20me is nominally 70–90% abundant per histone H4 molecule and there are two histone H4 molecules per nucleosome, there is on average more than one H4K20me per nucleosome [9, 10] ( see Table 1). This makes any independent function of this mark, without consideration of co-occurring PTMs, difficult to explain. This indicates that histone PTMs do exert their function individually
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
