RESEARCH

We utilize patient and human-derived induced pluripotent stem cells (hiPSCs) to create human-specific models of development and disease. In particular, we grow forebrain cortical brain organoids that recapitulate the subventricular zone and cortical layers of the human brain, allowing us to identify changes in neurogenesis and neural function across the complex tissue rather than more simple 2D models. We have been able to identify human-specific regulatory mechanisms of neurobiology that were not identified in mice. For example, we have found that mutations in an rRNA methyltransferase cause massive impairments in neural stem cell proliferation and differentiation due to altered translation of key transcripts throughout neural development. In parallel, we use our human brain organoids to study neural disorders ranging from Fragile X Syndrome to Alzheimer’s Disease. We collaborate by using our models to help identify small molecule or pharmaceutical drugs that can alter cellular symptoms of neural diseases.

We use a novel split GFP system to tag proteins of interest at their endogenous genomic loci. We then study the expression, localization, and enzymatic activity of these genes of interest to better understand the dynamic function of the epitranscriptome across developmental and disease contexts. We use CRISPR screening technologies to identify regulators, interactors, and drugs that can modulate expression or activity of our tagged targets.

“Epitranscriptomics” is a relatively new field that spans several disciplines to identify the molecular mechanisms and functional significance of chemical modifications on RNA. The discovery of RNA methyltransferases, demethylases, and modified-RNA binding proteins (“readers”) has transformed our understanding of how RNA processing in the cell regulates a myriad of processes, from neural development to cancer biology.

An important aspect of the epitranscriptome is that it is dynamic in nature- which gene transcripts are modified and the downstream effects of modification changes over developmental time, cell type, and in response to stimuli. We are particularly interested in understanding the regulation of the epitranscriptome- what prompts dynamic changes in the system that in turn regulate the way a cell responds to internal or external stimuli? Can these pathways be manipulated to alter cell behavior in development and disease?