Yen Laboratory
RNAs have rapidly emerged as the key players in many fundamental biological processes, as well as the bridge to future medicine. The Yen laboratory is interested in the biology of RNA molecular switches (riboswitch), small catalytic RNAs, alternative RNA splicing, and their applications in medicine. We use a variety of chemical and molecular biology strategies, in combination with mammalian cell cultures and animal models in pursuit of our goals.
The development of RNA-based molecular switches for gene regulation
The ability to control gene expression has always been indispensable in order to elucidate the function of a specific gene product, or to manipulate the levels of a specific protein to achieve therapeutic effects. A major focus of our lab is to harness the power of small catalytic RNAs (such as the hammerhead ribozyme) to create new RNA switches that can be turned on or off by small molecules. One of the strategies we use is illustrated in Figure 1. When a self-cleaving ribozyme is embedded in the mRNA, the spontaneous self-cleavage of ribozyme leads to destruction of the mRNA and therefore a loss of gene expression. Small molecules capable of inhibiting ribozyme result in preservation of the intact mRNA, and therefore induce gene expression. This strategy of RNA switches has the potential to lead to the creation of many tailor-made gene regulation systems, each controlled by a different small molecule. An important goal of our future research is to develop conditional RNA switches that can be turned on or off by FDA-approved small molecules. Such gene regulation systems, combining safe small molecules with non-immunogenic RNA switches, would be significantly safer to use in clinical applications as well as in biological studies.
Engineering RNA-based molecular biosensors
The small molecules used to control the RNA switch can be any cellular biomolecule, including metabolites, siRNA, miRNA, or proteins. In fact, it has been possible to engineer the ribozyme as a sensor to recognize a specific cellular ligand, and turn on a transgene according to the levels of the cellular ligand. We have great interest in exploring the engineering principles required to create sophisticated RNA switches that function as biosensors in vivo. Such biosensors would provide spatial as well as temporal information regarding the levels of specific ligands in disease, and the input information can be used to regulate cellular behavior for achieving therapeutic goals. For example, an RNA biosensor can be engineered to recognize glucose as its ligand, and in response, regulates the expression of an engineered insulin protein to modulate the glucose levels in diabetic patients (Figure 2). Similar biosensor platforms can also function as safety switches. For example, a biosensor can be engineered to detect the presence of a cancer biomarker in stem cells. When a normal stem cell erroneously transforms into a cancer cell, the biosensor would switch on a suicidal gene for self-destruction.
The identification of cancer biomarkers for diagnosis and therapy
Recent completion of Human Genome Project reveals that humans have far fewer genes than expected. The vast number of diversities in human proteins arise from alternative RNA splicing, a process that excludes or includes part of a gene to produce multiple protein isoforms from a single gene (Figure 3). The resulting isoforms can have different functions and are often an integrated part of early carcinogenesis. We are combining bioinformatics and high-throughput sequencing to identify cancer-specific protein isoforms. Such splice isoforms could potentially serve as biomarkers for early cancer detection, help to understand why some cells choose particular paths to carcinogenesis, as well as provide drug targets for cancer therapy.
Research Opportunities
We are looking for creative individuals to join our research team. Baylor College of Medicine is a world-renowned research institution located in the heart of the Texas Medical Center. Ample opportunities exist for scientific interactions with neighboring institutes such as MD Anderson Cancer Center, Rice University , University of Texas Health Center, and many research hospitals. The breadth and quality of biomedical science in the Texas Medical Center rivals that of any biomedical research center in the world. Our lab interacts regularly with several other labs in the Texas Medical Center including monthly joint lab meetings and a biweekly RNA journal club. If you are interested in RNA, and enjoy solving scientific puzzles, please contact:
Laising Yen, Ph.D.
Assistant Professor
Department of Pathology
Department of Molecular & Cellular Biology
Baylor College of Medicine
One Baylor Plaza , S234, BCM315
Houston , Texas 77030
yen@bcm.edu
To boldly go where no RNA has gone before