Mechanisms of chromatin and transcriptional regulation

Our long-term goal has been to reveal the molecular mechanisms of histone-modifying enzymes, histone chaperones and other transcriptional regulators that control genome function. Many of the proteins and their modifications we study are dysregulated in human disease, including cancer. Despite considerable progress by our lab and others, crucial knowledge gaps remain in our fundamental understanding of chromatin regulation. With the renewal of this MIRA award, we will continue our studies into the function of chromatin regulators and address three of the foremost fundamental questions in chromatin biology: 1) How do histone-modifying enzymes and chaperones contribute to chromatin organization and gene transcription? 2) How do more recently discovered histone PTMs and reader domains contribute to gene transcription? 3) What are the rules by which histone readers engage nucleosomes and how do these binding events regulate downstream events in chromatin? For each question, we highlight several examples of the types of studies we are pursuing and describe how they will advance the field.