Gene Regulatory Mechanisms—Implication for Medical Genomics
The proper execution of gene regulation is critical for human health and wellbeing; incorrect execution can lead to developmental defects and disease states. Over the course of his career, John T. Lis, Molecular Biology and Genetics, has worked to understand the basic gene regulatory mechanisms during the process of transcription—when genes are transcribed into RNA—during both normal and perturbed states. Such an understanding provides critical information for making precise diagnoses, developing highly specific therapies, and obtaining optimal patient outcomes in the emerging field of medical genomics.
In this project, Lis and his group are looking specifically at the regulatory effects of a key enzyme in gene transcription, RNA polymerase II (Pol II). In past studies of the heat shock genes in Drosophila, Lis’ group found that after the Pol II reaches its start-site on the DNA, called the promoter, it begins transcribing; but it reaches a pause site and stops. They further discovered that this pausing affects and regulates the rate and progress of transcription, which ran counter to established models that had assumed the most significant regulation occurred before elongation begins.
Now, Lis and his team are focusing their efforts on understanding the mechanisms underlying this pausing and the regulated escape of Pol II into productive elongation. They are examining the mechanisms at very high resolution in vivo under normal conditions and after specifically disrupting promoters, transcription factors (TFs), or TF interactions. These genome-wide data will be used to refine existing ideas and to generate new hypotheses for the mechanisms that contribute to the crucial and complex regulation of transcription. NIH Award Number: 2R01GM025232-40