Molecular Neurogenetics

To systematically model the genetic spectrum that are affected in human GBM, we use human iPSC-derived organoid to dissect the genetic heterogeneity in GBM. Using CRISPR/Cas9, we generated a spectrum of mutation combinations (Pten, Trp53, Cdkn2a, Cdkn2b, Nf1, Rb1, Egfr, Tert etc.), which are the most frequently mutated genes in human GBM (McLendon et al., 2008), in human iPSCs. We could induce GBM organoid from these cells, the GBM organoid (LEGO: Laboratory Engineered Glioma Organoid) derived from these cells recapitulate key molecular features of human GBM. We are using LEGO models to dissect the interaction between genetic heterogeneity and functional heterogeneity in GBM. Drug screen are also being conducted to build a genotype-based drug reference for personalized treatment of GBM.

We model the genetic spectrum altered in GBM in human iPSC-derived organoids to analyze genetic heterogeneity in GBM. Using CRISPR/Cas9, we generated a spectrum of mutation combinations in human iPSCs (Pten, Trp53, Cdkn2a, Cdkn2b, Nf1, Rb1, Egfr, Tert, etc.) that are currently the most frequently mutated genes in human GBM (McLendon et al., 2008). From these cells, we were able to induce GBM organoids (LEGO: Laboratory Engineered Glioma Organoid) that recapitulate the key molecular features of human GBM. We use these LEGO models to analyze the interaction between genetic heterogeneity and functional heterogeneity in GBM. Drug screening is also being conducted to establish a genotype-based drug reference for personalized treatment of GBM.

We generated a series of mouse models and human organoid models that allow us to precisely manipulate gene expression in neural stem cells and brain tumor stem cells. In this project, we are dedicated to unravel how the dynamic transcriptional regulations are involved in regulating the identity, activity and fate of NSCs. We are systematically analyzing the role of essential transcription factors and chromatin regulators in neurogenesis in order to generalize the molecular principles of cell identity determination. In particular we are interested in studying transcription regulators like Nr2e1 and Chd7 which are mutated in human neurological disorders and brain cancers.