  In lymphoma, mutations in genes of histone modifying proteins are frequently
observed. Notably, somatic mutations in the activatory histone modification
writing protein MLL2 and the repressive modification writer EZH2 are the most
frequent. Gain of function mutations are typically detected in EZH2 whilst MLL2
mutations are usually observed as conferring a homozygous loss of function. The
gain-of-function mutations in EZH2 provide an obvious target for the
development of inhibitors with therapeutic potential. To counter the loss of
functional MLL2 protein, we computationally predicted compounds that are able
to modulate the reader of the corresponding modifications, BPTF, to recognize
other forms of the histone H3 lysine 4, instead of the tri-methylated form
normally produced by MLL2. By forming a synthetic triple-complex of a compound,
the histone H3 tail and BPTF we potentially circumvent the requirement for
functional MLL2 methyl-transferase through the modulation of BPTF activity.
Here we show a proof-of-principle that special compounds, named variators, can
reprogram selectivity of protein binding and thus create artificial regulatory
pathways which can have a potential therapeutic role. A therapeutic role of
BPTF variators may extend to other diseases that involve loss of MLL2 function,
such as Kabuki syndrome or the aberrant functioning of H3K4 modification as
observed in Huntington disease and in memory formation.
