Grant: Project Grant

Although almost every cell in the human body contains the same genome, cells from different tissues express different sets of genes. This difference in gene expression patterns explains how heart cells but not brain cells beat in rhythm and how white blood cells fight invaders but muscle cells do not. At the center of gene expression patterns is the ability to turn genes on and off. Accurate control of gene expression is important for human health, as failure to turn genes on or off properly can lead to development defects, autoimmune disorders, and cancer. At the same time, modifying gene expression can be to our advantage: forced changes in gene expression is behind reprogramming, i.e. turning somatic cells into stem cells. Gene expression is regulated by proteins called transcription factors (TFs) that bind other genes' regulatory regions and instruct other proteins to activate or silence expression of these genes. However, although we know how to identify TFs and where in the genome many of them bind, we generally do not know if they activate transcription, repress transcription, or do both. In this proposal we will take a systematic approach to test all human proteins, including all TFs, for their ability to repress transcription. This will allow us to understand how TFs and other proteins in the human genome regulate the expression of other genes, and how they keep genes and larger genomic regions silent. Moreover, this research can help design better tools for cellular reprogramming in therapeutic applications.