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In lymphoma, mutations in genes of histone modifying proteins are frequentlyobserved. Notably, somatic mutations in the activatory histone modificationwriting protein MLL2 and the repressive modification writer EZH2 are the mostfrequent. Gain of function mutations are typically detected in EZH2 whilst MLL2mutations are usually observed as conferring a homozygous loss of function. Thegain-of-function mutations in EZH2 provide an obvious target for thedevelopment of inhibitors with therapeutic potential. To counter the loss offunctional MLL2 protein, we computationally predicted compounds that are ableto modulate the reader of the corresponding modifications, BPTF, to recognizeother forms of the histone H3 lysine 4, instead of the tri-methylated formnormally produced by MLL2. By forming a synthetic triple-complex of a compound,the histone H3 tail and BPTF we potentially circumvent the requirement forfunctional MLL2 methyl-transferase through the modulation of BPTF activity.Here we show a proof-of-principle that special compounds, named variators, canreprogram selectivity of protein binding and thus create artificial regulatorypathways which can have a potential therapeutic role. A therapeutic role ofBPTF variators may extend to other diseases that involve loss of MLL2 function,such as Kabuki syndrome or the aberrant functioning of H3K4 modification asobserved in Huntington disease and in memory formation.

New class of compounds - variators - are reprogramming substrate specificity of H3K4me3 epigenetic marks reading PHD domain of BPTF protein