Emerging Roles of Epigenetics in Development and Cancer

Nuclear receptors, including hormone receptors, activate transcription and reprogram genomes through collaboration with enormous coactivator complexes that recognize, bind and enzymatically modify histone tail residues. These receptors and coactivator complexes (known as COMPASS-like complexes) are critically important regulators of development and differentiation in all higher eucaryotes and disruptions of their functions are strongly linked to developmental defects and many cancers, including lymphoma, medullobastoma (brain tumor), breast, prostate and bladder cancers. Components of these coactivator complexes are strongly conserved throughout the animal kingdom, including MLL2/KMT2D) and its paralog MLL3/KMT2C that contain both chromatin recognition/binding and histone lysine methyltransferase domains. The genes encoding these proteins arose from a single common ancestor. In Drosophila and some other dipterans, this ancestral gene underwent a fission event, separating into two independent genes, cara mitad (cmi) and trithorax-related (trr). The CMI protein represents the N-terminal half of the MLL2 and MLL3 proteins protein and includes several epigenetic ‘reader’ PHD domains, while the TRR protein represents the C-terminal half and includes the histone methyltransferase activity. This natural split in a genetic model organism has allowed an important opportunity to explore the unique functions of the conserved domains in regulating nuclear receptor functions during development and may allow insights into the roles of nuclear receptor coactivators in human disease. We are currently focused on comparing the unique and conserved chromatin recognition and binding properties of both the Drosophila and human ALR/MLL family PHD fingers using genetics, chromatin binding assays, biophysical measurements and X-ray crystallography/structural biochemistry. Using ChIP-seq and RNA-seq analyses and in vivo reporter gene assays, we are identifying all of the genomic targets of the complex so that we can identify how and when the complex activates or blocks gene expression.