RNA Polymerase III Transcription in Health and Disease
Our laboratory studies gene transcription by RNA polymerase (Pol) III and the functional impact of this system on normal and disease processes. The products of Pol III transcription are small non-coding RNAs that have diverse and expanding functions in eukaryotic cells. These include RNAs that are central players in cell growth, notably in protein synthesis, and molecules that function in RNA processing, protein secretion and in various regulatory capacities. Proper regulation of Pol III transcription is critical for balanced growth and its deregulation is a key event in cell transformation and tumorigenesis. For these and other reasons, much of our research has focused on the Maf1 protein, a master negative regulator of Pol III transcription, and its posttranslational control by nutrient- and stress-signaling pathways. Our programs span genetics, molecular biology, biochemistry, metabolism and structural biology and utilize budding yeast and mice as model experimental systems. Two important areas of concentration are highlighted below.
Mechanisms of Obesity Resistance in Maf1 Knockout Mice
Mice with a whole body knockout of Maf1 are resistant to diet-induced obesity and have increased healthspan. Obesity resistance in these mice is associated with increased energy expenditure and metabolic inefficiency. Our current mechanistic understanding of these phenotypes is based on a novel futile RNA cycle hypothesis wherein deregulated Pol III transcription serves as an energy sink, consuming energetically costly nucleotides in the wasteful synthesis of RNA that does not accumulate and is mostly degraded. Current research on this unique model is focused on understanding global (whole body) and cell-specific molecular and metabolic changes that enhance energy expenditure and contribute to the lean phenotype. We are also exploring the possibility that MAF1 may be targeted therapeutically to treat obesity and improve healthspan.
Mechanisms of Neurodegeneration in Pol III-related Leukodystrophy
Pol III-related leukodystrophy was recently identified as a genetically inherited neurodegenerative disease. The early-onset form of the disease manifests in children as a progressive decline in motor function, cognitive regression and intellectual disability with variable neurological and non-neurological features. We have developed a mouse model of this disease and have characterized numerous behavioral and neuropathological phenotypes. Our research seeks to understand the mechanisms of pathogenesis in different neural cell populations and their molecular basis. The work is currently focused on the oligodendrocyte lineage since hypomyelination is a hallmark of the disease in patients and in the mice.