Gene regulation in cancer, RNA processing; Epigenetic modification; Stem cell and development
One of the central paradigms is that genes are located in isolated zones, minding their own business (making their own RNAs and proteins) and don?t usually cross talk with each other, except in pathological situations. For example, one of the hallmarks in cancer is DNA rearrangement, which results in the fusion of two separate genes. These gene fusion products often play critical roles in cancer development. Traditionally, they are thought to be the sole product of DNA rearrangement and therefore unique to cancer. This belief forms the basis for many cancer diagnostic and therapeutic approaches. Recently, we discovered two mechanisms that could generate fusion products without DNA rearrangement. One of the process is called ?RNA trans-splicing?, whereby two separate RNAs can be spliced together and generate a fusion RNA, which then can be translated into a fusion protein. The other process involves two neighboring genes transcribing in the same direction, ?cis-Splicing of Adjacent Genes (cis-SAGe). Our work on RNA trans-splicing and intergenic cis-splicing have posed a challenge to the traditional views and helped open a new paradigm for intergenic splicing processes that generate gene products in normal physiological conditions: even in the absence of physically ?touching? each other, genes do send messages (messenger RNA) that can be mingled together. These mechanisms may also be ways to expand out functional genome, and explaining the enigma that human and mouse, even worm share a similar number of genes. Our long-term goals are to understand the scope of these phenomena, the physiological functions of these ?intergenic splicing? process and their implications in both normal development and in cancer. We are using a wide range of approaches ranging from state-of-art bioinformatic pipeline to modified CRISPR/CAS9 systems. Another direction we are taking is more translational. Oncogene addiction is a principle important for basic understanding of tumorigenesis and cancer therapy. The challenge is to find such key oncogenes. Even though large sets of genome and transcriptome data are available to facilitate such discovery, true signals are often buried in a large number of passenger events. On the other hand, we know that a key oncogene could be dysregulated by different mechanisms in different cancer types. However this knowledge is usually accumulated through years of study and often involves different labs working on different cancer. Our strategy is to use this concept proactively to find key oncogenes that cancer cells become addicted to. Our strategy startes from pediatric tumors with relatively simple genomic landscape, find a key gene fusion, and extend to adult tumors. We have found a novel oncogene and proved its critical role in gliblastoma.