Welcome to the Boutz Lab
RNA processing plays an essential role in virtually any cellular process--from the differentiation and maintenance of the specialized functions of normal tissues, to the development and progression of human diseases such as cancer. It is increasingly evident that many small molecule drugs affect global gene expression though RNA processing mechanisms to alter the physiology of cells, and very recently, drugs that directly target RNA and RNA-protein complexes have become an area of great interest.
In our group we implement a multi-disciplinary approach that includes molecular biology, genomics, bioinformatics, and state-of-the-art genome engineering to understand the essential roles of RNA processing in normal and tumor cell physiology, and to uncover the molecular mechanisms by which drugs alter gene expression. Our group seeks to develop new molecular technologies as well as novel computational approaches to advance our exploration of uncharted biological territory. Ultimately, our goals include using genomics to gain mechanistic insight into how the RNA processing machinery functions, enabling the development of more potent and specific therapeutics, and advancing the use of genomic data for personalized medicine--identifying the patients who are most likely to benefit from targeted therapy.
Mutations in core components of the spliceosome occur frequently in many types of cancer, yet the mechanism by which these mutations affect tumor cell physiology is a major outstanding problem in the field. One major focus of our group is to understand how these mutations change the function of the spliceosome to allow tumor cells to bypass a “splicing checkpoint”. This checkpoint may involve one or several splicing regulators that control structural rearrangements of the spliceosome, and thus may represent a druggable target in tumors carrying these mutations. Through the study of mutation-dependent alteration of spliceosome function, we also stand to gain further insight into how splicing is regulated under normal physiological conditions.
We recently found that a kinase called CDK12 suppresses the use of polyadenylation sites located within the introns of genes. Intronic polyadenylation (IPA) is another form of RNA processing that results in the production of shorter, unstable mRNAs at the expense of the full length gene product. Through this mechanism, CDK12 functions as a master regulator of the homologous recombination pathway. Cancer cells that have mutations in CDK12, or that are exposed to drugs that inhibit its activity, are highly sensitive to certain chemotherapy drugs and to immunotherapies, and thus CDK12 is a high priority drug target. We are interested in how CDK12 mutations in prostate, ovarian, and breast cancer affect the progression of tumors and the development of therapeutic resistance. Using IPAs as a novel biomarker, we hope to be able to identify tumors that, due to CDK12 loss-of-function, are particularly sensitive to genotoxic drugs as well as immunotherapy.
A third core focus of our group is on a novel type of RNA processing that we recently characterized called ‘detained introns’ (DIs)--individual introns present in otherwise fully-spliced, polyadenylated transcripts. Through intron detention, cells can modulate the rate of splicing to directly control the amount of mature mRNA available for encoding protein. Drugs that inhibit protein-modifying enzymes including CLK kinases, PRMT5 (arginine methyltransferase) and OGT (O-linked N-acetylglucosamine transferase) can affect the splicing of DIs. Our goals include understanding, at the molecular level, how DIs are regulated, and how factors that promote human disease affect DI splicing by modulating the ‘splicing capacity’ of cells to coordinate the control of large, functionally related gene sets. Ultimately, understanding this novel gene regulation pathway could expedite the development of small-molecule drugs to counter human diseases including cancer.