Arrangement of DNA into chromatin and epigenetic organization is achieved by the combined action of histone and other DNA binding proteins as well as many regulatory enzymes/proteins. These chromatin organizing or epigenetic regulators are essential not only for gene expression but also for the underlying DNA stability, integrity and accurate replication in the context of complex genomes.
Over the past years our understanding of modular epigenetic regulators containing targeting motives and/or catalytic domains has greatly increased. Some protein domains such as Plant Homeo Domains (PHD), Malignant Brain Tumours (MBT) or Bromodomains (BRD) direct the proteins to particular binding sites in the chromatin, whereas others such as Su(var)3-9, Enhancer-of-zeste and Trithorax (SET) or Jumonji (JMJ) domains ensure that an appropriate genomic site is marked with an activating/repressive or cell cycle appropriate mark. Drawing on the SGC’s structural biology expertise and available functional information we examine the function of the epigenetic modulators by using genetic knockdown and chemical probe/inhibitor approaches. The essential part of this functional investigation is the design of robust cellular assays that guide chemical probe development. Given the wide variety of cellular processes epigenetic regulators take part in, functional consequences such as influence on include gene expression, genome-wide localization, cell cycle progression, DNA replication and repair can be assessed.