Studies on SWI/SNF in 3D chromatin structure with viral epis

Complete genomic DNA sequencing reveals that the human genome contains about 20,000 of protein coding genes. By comparing healthy cells with cancer cells, researchers are identifying the genes that are responsible for causing cancers. Cancer is characterized by abnormal cell growth with the potential to invade or spread to other parts of body. Normal cells become cancerous when they lose their ability to communicate with surrounding cells. Cells are continuously receiving information from neighboring cells and respond by extracting the necessary information from their own DNA to produce the correct proteins in coordinated manner. Thanks to advancement of technology, our understanding of cancer DNA has reached the point where we can predict which genes are responsible for interfering with the communication process. We are now in a position to examine why some of genes are very frequently disrupted in cancer cells and to identify the function of their proteins in normal cells.
Among many of disrupted genes in cancer cells, a large protein complex named SWI/SNF was identified to be disabled in more than 20% of cancer cells. The SWI/SNF complex is an enzyme complex that makes DNA accessible to other protein.

Our studies on Kaposi's sarcoma-associated herpesvirus (KSHV) showed SWI/SNF complexes interact with RNA polymerase II, a key enzyme for generating RNA from DNA. In addition, we found a number of DNA loops formed when DNAs were transcribed with RNA polymerase II. DNA loops are important for coordinated DNA transcription and we think that the SWI/SNF complex performs an important function in gene coordination by connecting distantly located DNAs by creating physical DNA looping. Because this is a fundamental role in biology, we think that disruption of key SWI/SNF component will cause miscommunication in cancers. In this project, I will study the biological function of SWI/SNF in DNA looping formation and communication between genes. We have generated unique tools to study this communication. We will use mini viral chromosomes as a model to study the normal function of the complex. My primary goal is to provide insights as to why deregulation of SWI/SNF complex associates with cancer.