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

TL;DR

This paper introduces variators, novel compounds that reprogram the substrate specificity of BPTF's PHD domain to recognize different H3K4 methylation states, offering potential therapeutic strategies for diseases involving MLL2 mutations.

Contribution

The study demonstrates that variators can selectively alter BPTF's recognition of histone modifications, creating artificial regulatory pathways with therapeutic implications.

Findings

Variators successfully reprogram BPTF substrate recognition.

Potential to bypass MLL2 loss of function in diseases.

Implications for treating conditions like Kabuki syndrome and Huntington disease.

Abstract

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.