Research Interests

A Systems Biology Approach to Diagnosis, Understanding, and Treatment of Autism Spectrum Disorders

We are using large-scale gene expression profiling of lymphoblastoid lines from autistic individuals and controls to probe for biomarkers and pathways relevant to autism spectrum disorders (ASD). However, 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, 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 questionnaire, 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 group-defined genes reveal biological deficits that may be specific targets for therapy for each of the respective subgroups. Circadian rhythm genes are among the group-specific targets that are differentially expressed only in the phenotype of ASD with severe language impairment. Our studies also show the overlap of differentially expressed genes between the groups, suggesting common genes involved in the core symptoms of ASD. 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 gene expression profiling.

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 (Ref. 1) 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 continuing to examine the role of specific changes in methylation and microRNA expression in relation to ASD

Selected Publications (most recent):

1. 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. ?(2009) Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: ?Altered pathways in neuronal development and steroid biosynthesis. ?PLoS ONE, in press

2. Hu, V.W., Sarachana, T., Kim, K.S., Nguyen, A., Steinberg, M.E., Luu, T., Lai, Y., and Lee, N.H. (2009) 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(2), in press

3. Hu, V.W. and Steinberg, M.E. (2009) Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders. Autism Research 2(2), in press

4. Hu, V.W., Frank, B.C., Heine, S., Lee, N.H., and Quackenbush, J. (2006) 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. <www.biomedcentral.com/1471-2164/7/118>

5. Marko, N.F., Dieffenbach, P.B., Yan, G., Ceryak, S., Howell, R.W., McCaffrey, T.A., and Hu, V.W. (2003) 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.

6. Hu, V.W., Black, G.E., Torres-Duarte, A., and Abramson, F.P. (2002) ³H-thymidine is a defective tool with which to measure rates of DNA synthesis. FASEB J. 10.1096/fj.02-0142fje [FASEB J. on-line express]

7. Hu, V.W., Heikka, D.S., Dieffenbach, P.B., and Ha, L. (2001) Metabolic radiolabeling: experimental tool or Trojan horse? ³⁵S-methionine induces DNA fragmentation and p53-dependent ROS production. FASEB J. 15:1562-1568

We are grateful to Turner BioSystems for granting us a Veritas Microplate Luminometer which is being used for our studies on ASD.