Ph.D. in Internal Medicine, Jinan University, 2010
M.S. in Biochemistry, Jinan University, 2005
M.D. in Clinical Medicine, Tongji Medical University, 2002
2011-2013: Postdoctoral fellow at the Wang Genomics Lab
Associate Professor, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University
functional genomics studies of autism candidate genes in neural stem cells, next-generation sequencing on autism families
Functional genomics of autism candidate genes
Genetic mutations in NLGN4X (neuroligin 4), including point mutations and copy number variants (CNVs), have been associated with susceptibility to autism spectrum disorders (ASDs). However, it is unclear how mutations in NLGN4X result in neurodevelopmental defects. Here, we used neural stem cells (NSCs) as in vitro models to explore the impacts of NLGN4X knockdown on neurodevelopment. Using two shRNAmir-based vectors targeting NLGN4X and one control shRNAmir vector, we modulated NLGN4X expression and differentiated these NSCs into mature neurons. We monitored the neurodevelopmental process at Weeks 0, 0.5, 1, 2, 4 and 6, based on morphological analysis and whole-genome gene expression profiling. At the cellular level, in NSCs with NLGN4X knockdown, we observed increasingly delayed neuronal development and compromised neurite formation, starting from Week 2 through Week 6 post differentiation. At the molecular level, we identified multiple pathways, such as neurogenesis, neuron differentiation and muscle development, which are increasingly disturbed in cells with NLGN4X knockdown. Notably, several postsynaptic genes, including DLG4, NLGN1 and NLGN3, also have decreased expression. Based on in vitro models, NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. Our functional genomics study highlights the utility of NSCs models in understanding the functional roles of CNVs in affecting neurodevelopment and conferring susceptibility to neurodevelopmental diseases.
Next-generation sequencing on autism families
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism.
To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes.
By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies.
Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases.
- Ling C, Pease M, Shi L, Punj V, Shiroishi MS, Commins D, Weisenberger DJ, Wang K*, Zada G*. A Pilot Genome-Scale Profiling of DNA Methylation in Sporadic Pituitary Macroadenomas: Association with Tumor Invasion and Histopathological Subtype. PLoS ONE, 9: e96178, 2014
- Gao F, Ling C, Shi L, Commins D, Zada G, Mack W, Wang K. Inversion-mediated gene fusion involving NAB2-STAT6 in an unusual malignant meningioma. British Journal of Cancer, 109:1051-1055, 2013
- Chang X, Shi L, Gao F, Russin J, Zeng L, He S, Chen TC, Giannotta SL, Weisenberger DJ, Zada G, Wang K*, Mack WJ*. Genomic and transcriptomic analysis reveals an oncogenic functional module in meningiomas. Neurosurgical Focus, 35:e3, 2013
- Shi L, Chang X, Zhang P, Coba M, Lu W, Wang K. The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells. Human Molecular Genetics, 22:3749:3760, 2013
- Shi L, Zhang X, Golhar R, Otieno FG, He M, Hou C, Kim C, Keating B, Lyon GL, Wang K*, Hakonarson H*. Whole-genome sequencing in an autism multiplex family. Molecular Autism, 4:8, 2013
- Zeng L, Zhang P, Shi L, Yamamoto V, Lu W*, Wang K*. Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models. PLoS ONE, 8:e59685, 2013
- Gao F, Shi L, Russin J, Zeng L, Chang X, He S, Chen TC, Giannotta SL, Weisenberger DJ, Zada G, Mack WJ, Wang K. DNA methylation in the malignant transformation of meningiomas. PLoS ONE, 8:e54114, 2013