Molecular Phenotypes of Structurally Homologous ETS Transcriptions Factors

 ETS transcription factors comprise an evolutionarily related family of genetic regulators that are ubiquitous in animals and control a myriad of physiologically critical processes. ETS proteins are united by a highly conserved DNA-binding domain, with overlapping target DNA preferences on the one hand, but are functionally diverse and non-redundant on the other. This so-called ìspecificity conundrumî besets not only our understanding of ETS homologs but also the structure-activity relationships of eukaryotic transcription factors in general. Translationally, it hampers efforts to develop chemical biology for transcriptional control. Our recent work on model ETS proteins has revealed several novel molecular phenotypes that relate to their functional heterogeneity in terms of sensitivity to epigenetically modified DNA, self-regulation, and restriction by heterochromatin. Understanding the mechanistic bases of these molecular phenotypes will significantly advance our understanding of how ETS proteins evolve a conserved scaffold to achieve distinct functions and help fulfill their potential as highly desirable drug targets.