Epigenetic control is essential for maintaining transcriptional integrity. Regulation of the dynamicepigenome is mediated through a range of post translational modifications on DNA and histonetails. Histone modifications are mediated by enzymes which can be broadly classified into "writers"that catalyze the addition of chemical modifications, "erasers" that remove the modifications, and"readers" that can recognize chemical modifications through specific protein domains. The writingand erasing of histone marks by enzymes is a dynamic process, and when dysregulated isassociated with cancer, inflammatory and neurological diseases.In this application we focus on the two classes of histone modifying enzymes, lysine methyltransferases (KMTs) and lysine demethylases (KDMs), and aim to develop and validate cell-based assays targeting both KMTs and KDMs. These assays, based on a three-hybrid splitluciferase system, are reversible allowing dose dependent quantification of inhibitor binding.These efforts are both significant and innovative as they can report on the direct binding of a drugto the target protein at its intended site of action, thereby facilitating the generation of leadtherapeutic candidates and identification of chemical probes for studying histone biology andpathways.
Public Health Relevance Statement: Project Narrative
Epigenetic gene regulation is important for many fundamental processes in a cell, and
dysregulation is commonly associated with brain diseases and cancer. Development of assays
against new epigenetic targets will help advance the discovery of new and effective therapies.
The purpose of this application is to develop low-cost assays, using our platform technology, for
two such epigenetic targets, the histone methylating and demethylating enzymes.
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