Grant: Project Grant

Most of the mutations that cause various kinds of human disease lie outside the 1% of the human genome that codes for proteins and instead lie in DNA sequences that probably control the expression levels of the various human genes. Such gene-regulating sequences are usually recognized by the ~1600 different human transcription factors, of which ~700 contain "zinc fingers" and are poorly understood. We have discovered that the zinc finger proteins do indeed recognize particular DNA sequences to control the transcription of human genes but also that they tend to interact with each other and with RNA, as well as DNA. We will now determine how the multi-factorial interactions of the zinc finger proteins are coordinated to enable them to bring different DNA sequences together to organize the shape of the human genome and regulate the initiation and termination of transcription, as well as how the resulting transcripts are spliced. Understanding how these zinc finger proteins work, when matched to ongoing world-wide genome sequencing experiments to identify mutations that cause human disease, will provide important information about many human diseases, including very important multi-factorial diseases like cancer, heart disease, and diabetes.