The research in Zhao laboratory focuses on understanding the molecular mechanisms that regulate neural stem cells and neuronal development, with the goal of developing better treatment for neurodevelopmental and neurological disorders. We use transgenic mice, human pluripotent stem cells (iPSCs, ESCs), patient-derived and CRISPR gene-editedstem cells, and 3D forebrain organoids, as model systems. We employ cutting edge single-cell and cell type-specific -omics (e.g. single cell/single nucleus RNA-seq/ATAC-seq, Patch-seq, RiboTag-seq, TRAP-seq, proteomics, etc), fluorescent imaging, and behavioral methods to interrogate the roles of genes, epigenetic regulators, RNAs, and proteins in neuronal development. We determine how the mutations of these regulators may contribute to brain disorders and identify potential therapeutic targets and treatment methods. Our projects are continuously evolving with our current research effort directed towards several central questions:
- We investigate the functions of specific genetic and epigenetic regulators and RNA binding protein translational regulators in neuronal development and how their mutations lead to neurodevelopmental disorders.Epigenetic mechanisms, acting through DNA methylation and chromatin remodeling, have profound regulatory roles in mammalian gene expression. We have been studying how mutations in epigenetic regulators lead to altered gene expression and impaired neuronal development in the context of Rett syndrome and autism.
Post-transcriptional gene regulations are mediated by complex mechanisms, including noncoding RNAs (e.g.microRNAs) and RNA-binding proteins (e.g. FMRP, FXR1, FXR2). One major area of our study is to investigate the function of neuronal RNA-binding proteins in neuronal development and pathogenesis of neurodevelopment disorders such as fragile X syndrome.
- We interrogate the complex relationships between gene expression, neuronal plasticity, neural circuit, and behavior.Identification of the gene regulatory networks in responses to environmental signals, comparison among these gene networks, and construction of predictive models of global circuit behavior from these networks are among the biggest questions of modern neuroscience. We hypothesize that the genetic or epigenetic mediators of Gene X Environment interactions are likely cell type-specific and brain circuit-specific. Together with my collaborators, we use cutting edge Patch-seq, single nucleus Multiomics (RNA-seq/ATAC-seq of the same nucleus), and cell type specific translational profiling, imaging, and network modeling methods to answer these questions.