Mechanisms of eukaryotic transcription
Gene transcription allows cells to ‘read’ the information encoded in the DNA and thus initiate production of proteins which carry out all cellular processes. Perturbations in regulation of gene transcription are a common cause of human diseases, including cancer. Using their pathologic transcriptional programs cancer cells can grow and proliferate outside of the natural limits. At the same time, they often become over-dependent on specific proteins or regulatory pathways which creates opportunities for development of targeted therapies once we understand the details of these mechanisms.
In all eukaryotic organisms, from simple unicellular yeast to humans, DNA is stored as chromatin which consists of a DNA strand wrapped around bead-like structures made of histone proteins. The histone octamer and a section of a DNA strand associated with it are called a nucleosome. Cells carefully regulate nucleosome positioning because nucleosomes can restrict transcription by limiting the access of transcription factors and RNA polymerase II to DNA. Additionally, many proteins involved in transcription and other cellular processes can ‘read’ specific modifications on histone proteins which are dynamically deposited and erased by other specialized factors.
Our lab studies complex mechanisms which regulate gene transcription in a dynamic chromatin environment. We are especially interested in early stages of transcription called initiation and elongation, both of which involve a broad repertoire of transcription factors and chromatin modifying complexes. Our flagship project is focused on chromatin readers from the BET family, which translate acetylated states of transcription factors and histones into a specific transcriptional output. BET factors were recognized as attractive drug targets for many types of cancer and immunoinflammatory conditions, but their regulation and roles are poorly understood, which limits drug discovery efforts. We recently found that yeast BET factors Bdf1/2 have roles in transcription which are similar to their human equivalents. Yeast cells have a long history as an excellent model used to understand the functions of human cells. We are now utilizing both yeast and mammalian models to reveal fundamental and conserved mechanisms of transcription facilitated by BET proteins and other factors, and to provide the basis for development of new targeted therapies.