Director, Stem Cell Program at the Institute for Cell Engineering; Professor, Department of Neurology
We are interested in understanding novel mechanisms regulating structural and functional plasticity in the mature mammalian center nervous system. There are two major topics in the laboratory: one is on adult mammalian neural stem cells and neurogenesis; and the other is on epigenetic DNA modifications in the mature nervous system. Our laboratory is using integrated approaches to address the questions, including technologies in molecular biology, cell biology, biochemistry, epigenetics, genomics, bioinformatics, virology, histology, in vivo multiphoton confocal imaging, electrophysiology, mouse genetics and animal behaviors.
(1). Adult neural stem cells and neurogenesis: Adult neurogenesis occurs in unique microenvironment (niche) and recapitulates the complete neural developmental process in a mature central nervous system, including proliferation and differentiation of neural progenitor/stem cells, neuronal development and synapse formation, maturation and maintenance. Using retrovirus- and mouse genetics-based strategies, we are interested in identifying both intrinsic and extrinsic mechanisms regulating behaviors of adult neural stem cells and governing synaptic integration of newborn in the adult brain in vivo. In addition, we are addressing the function of adult neurogenesis at multiple levels, including single-cell electrophysiology in acute slices, optogenetics and multi-electrode recordings in vivo, and animal behavior analysis.
(2). Epigenetic DNA modifications in neurons: DNA methylation at 5-cytocine has been traditionally considered as very stable epigenetic marks in post-mitotic cells. We recently show that neuronal activity induces active DNA demethylation in post-mitotic neurons in the adult brain in vivo. We further identified an activity-induced active DNA demethylation pathway in neurons, involving conversion of 5-methylcytosine to 5-hydroxylmethylcytosine by TET, followed by deamination by APOBECs and base-excision repair. We are interested in identifying molecular machinery mediating active DNA demethylation in neurons and the potential functions of DNA demethylation in neuronal plasticity and mental disorders. We are using combinatory approaches to address these fundamental questions, including biochemistry, protein chip, RNA-seq, Bisulfite-seq, Chip-seq, electrophysiology and animal behavior.