California Institute of Technology
Dark proteome-mediated transcriptional control at single-molecule resolution
Known as the “dark matter of biology” or the “dark proteome”, intrinsically disordered protein regions (IDRs) do not have clear structures and thus cannot be understood by conventional analysis. Although IDRs constitute nearly half of all the human proteins and play an important role in numerous cellular processes, the mechanisms underlying their functions remain largely elusive. Because dysregulation of IDRs can lead to many human diseases, e.g., cancers and neurodegenerative disorders, our incomplete understanding of IDR functions represents a major hurdle for understanding these pathological mechanisms and developing therapeutics.
We strive to understand how IDRs perform biological functions under normal and disease conditions. We currently focus on elucidating how they regulate transcription, the first step of gene expression in which a particular segment of DNA is copied into RNA. We are studying a number of aberrant, cancer-causing transcription factors, which contain IDRs that play critical functional roles with unclear mechanisms. Our work has the potential to both reveal fundamental principles in gene regulation and shed new light on cancer mechanisms and therapeutics. Because biomolecular transactions are often highly dynamic, reversible, and heterogeneous, an in-depth mechanistic understanding of these transactions requires visualizing biomolecules one at a time with high spatiotemporal resolution. To this end, we develop novel live-cell single-molecule imaging methods and combine them with genome editing, biochemical, genomic, proteomic, and chemical biology approaches in our research.
Although we initially focus on IDRs involved in transcription, the approaches and insights we develop will be broadly applicable to the study of the entire dark proteome. Ultimately, we aim to reach a comprehensive understanding of IDRs that allows prediction of protein functions from their amino acid sequences. In short, our multi-disciplinary research program tackles fundamental and long-standing questions in gene regulation and intrinsically disordered protein biology and promises to impact a broad range of biomedical fields.