Thomas Tuschl, Ph.D.
Investigator, Howard Hughes Medical Institute
RNA functions not only as a carrier of genetic information, but also as a catalyst and guide for the processing or regulation of other RNA molecules. Tuschl is investigating gene-regulatory mechanisms that include non-coding RNA and RNA-binding proteins in human cells, with the goal of developing treatments for genetic diseases.
Eukaryotic cells express a variety of classes of small RNA molecules. The Tuschl lab has identified these classes and their many members using various RNA-sequencing (RNA-seq) techniques. Their discoveries include the molecular characterization of small interfering RNAs (siRNAs), a class of double-stranded, 21-nucleotide-long molecules that guide sequence-specific gene silencing. Tuschl was the first to demonstrate their utility for knocking down human gene expression.
Two additional RNA classes uncovered by his lab, called microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), have great importance to human biology.
Hundreds of human miRNA genes with cell-type-specific expression patterns have been identified. Involved in many biological processes, miRNAs act by controlling messenger RNA stability in hundreds of targets. Because they are present in biofluids such as plasma and urine, miRNAs may serve as biomarkers of disease. The Tuschl laboratory developed automated processes to isolate and characterize extracellular small RNAs, and discovered remarkable changes in extracellular miRNA composition in normal and disease states.
piRNAs are specifically expressed in male and female germ line cells and are required for normal germ cell development. Although researchers know that knocking out the piwi protein-coding genes in mice causes male infertility, the targets and molecular function of piRNAs remain unknown. Efforts to characterize their biogenesis and targets are ongoing.
During its life cycle, messenger RNA interacts in a sequence-specific manner with many ribonucleoprotein complexes (RNPs) and RNA-binding proteins (RBPs). In order to understand these complex regulatory networks, the Tuschl lab has developed experimental approaches to precisely define the binding sites of RNPs and RBPs on coding and non-coding RNA and its precursors. Current studies focus on characterizing RBPs implicated in genetic diseases such as fragile X syndrome as well as those with unknown functions. The identification of RNA interaction networks sheds light on the biological function of these proteins and may contribute to the design of new therapeutic agents for controlling gene expression.
The Tuschl lab catalogs and annotates all cellular coding and non-coding RNAs in a global effort to clarify their roles in human development and various diseases. The ultimate goal is to host and mine all existing RNA-seq information in a database searchable by read, and to establish a non-redundant human reference transcriptome. As the project nears completion, residual unmapped reads hold promise for the discovery of new pathogens or rare genetic aberrations contributing to disease.
RNAs have been difficult to visualize and measure in archival tissue sections using traditional histological techniques. The lab continues to develop fluorescence-based methods to visualize RNA molecules in tissue sections while also exploring single-cell RNA-seq methods for characterization. This work will help researchers better understand the crosstalk occurring among cell types in inflammatory diseases and cancer.