Research Interests

The wide diversity in the manifestation and severity of the symptoms of autism has posed a significant challenge to the identification of genes that are responsible for, or diagnostic of, autism spectrum disorders (ASD). By dividing the autistic population into subgroups that are similar in severity across over 60 unique behavioral symptoms that are queried on a commonly used diagnostic assessment instrument, we have been able to identify genes that define each subgroup on the basis of differential gene expression relative to nonautistic controls. These sets of subgroup-defined genes reveal biological deficits that may be specific targets for therapy for each of the respective subgroups. Furthermore, we have found that the differentially expressed genes can distinguish samples from autistic and non-autistic individuals with greater than 94% accuracy, demonstrating the potential for a diagnostic test based upon these biomarker genes.

Another interest of the laboratory is higher order regulation of gene expression in ASD. Our earlier observation of differential gene expression between monozygotic twins discordant in diagnosis or severity of autism suggested the role of epigenetic factors in autism. We are therefore also studying the involvement of DNA methylation and microRNA expression in the regulation of gene expression in ASD. Our preliminary results show evidence of global methylation changes as well as significant differences in microRNA expression which can be at least partially correlated with the observed changes in gene expression. We are also developing cellular models to explore how these molecular changes impact neuronal survival, differentiation, and function and how environmental factors affect these processes.

Selected Publications

• Nguyen, A., Rauch, T.A., Pfeifer, G.P., and Hu, V.W. (2010) Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J., Published online Apr. 7, 2010. http://www.faseb.org; doi: 10.1096/fj.10-154484
• Sarachana, T., Zhou, R., Chen, G., Manji, H.K., and Hu, V.W. (2010) Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders (ASD) by microRNA expression profiling of lymphoblastoid cell lines. Genome Medicine, Published online Apr. 7, 2010. http://genomemedicine.com/content/2/4/32
• Hu, V.W., Nguyen, A., Kim, K.S., Steinberg, M.E., Sarachana, T., Scully, M.A., Soldin, S.J., Luu, T., and Lee, N.H. Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: Altered pathways in neuronal development and steroid biosynthesis. PLoS ONE, 4(6): e5775, 2009. doi:10.1371/journal.pone.0005775
• Hu, V.W., Sarachana, T., Kim, K.S., Nguyen, A., Steinberg, M.E., Luu, T., Lai, Y., and Lee, N.H. Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: Evidence for circadian rhythm dysfunction in severe autism. Autism Research 2:78-97, 2009.
• Hu, V.W. and Steinberg, M.E. Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders. Autism Research 2:67-77, 2009.
• Hu, V.W., Frank, B.C., Heine, S., Lee, N.H., and Quackenbush, J. Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genomics 7:118, 2006.
• Marko, N.F., Dieffenbach, P.B., Yan, G., Ceryak, S., Howell, R.W., McCaffrey, T.A., and Hu, V.W. Does metabolic radiolabeling stimulate the stress response? Gene expression profiling reveals differential cellular responses to internal beta vs. external gamma radiation. FASEB J. 17:1470-1486, 2003.
• Hu, V.W., Heikka, D.S., Dieffenbach, P.B., and Ha, L. Metabolic radiolabeling: experimental tool or Trojan horse? 35S-methionine induces DNA fragmentation and p53-dependent ROS production. FASEB J. 15:1562-1568, 2001.