Kevin Van Bortle

RNA polymerase III transcription regulation and small noncoding (nc)RNA biology

Our lab is primarily focused on addressing fundamental questions about RNA polymerase III (Pol III) transcription: which genes it transcribes, how its activity is regulated across cell types, and how its RNA products influence cell function. Despite Pol III’s essential role in producing small noncoding RNAs such as tRNAs and 5S rRNA, it remains surprisingly understudied, partly due to technical challenges related to its repetitive gene targets and short, chemically modified RNAs. Yet, Pol III overactivity is a recurring feature in cancer and other disease contexts, highlighting the importance of understanding its regulation. We are developing tailored genomic and biochemical approaches to overcome these barriers and build a comprehensive, functional view of Pol III transcription across diverse biological settings.

Our recent work has revealed unexpected Pol III activity at previously unannotated noncoding RNA genes and uncovered novel interactions between Pol III and Pol II transcriptional programs. We have also identified Pol III-derived small RNAs that influence RNA processing and splicing, pointing to roles that extend beyond classical models of Pol III function. These findings continue to challenge the traditional view of Pol III as a static “housekeeping” enzyme and instead position it as a dynamic regulator that is integrated into broader gene expression networks in a cell type- and context-specific manner.

Looking ahead, our research is aimed at defining how Pol III transcription is shaped during development, differentiation, and disease. We are particularly interested in how chromatin context and regulatory proteins modulate Pol III activity, and how misregulation of this system contributes to pathological states. By combining genome-scale profiling, functional genomics, and mechanistic studies, we aim to expand the conceptual framework for Pol III biology and uncover new principles of RNA-based regulation in human cells.