Faculty Directory

Valerie Hu

Valerie Hu

Professor of Biochemistry and Molecular Medicine

Office Phone: 202-994-8431
Email: Email
Department: Biochemistry and Molecular Medicine

Education

  • BS, University of Hawaii, 1972
  • PhD, California Institute of Technology, 1977

Biography

Valerie W. Hu, Ph.D., is a Professor of Biochemistry and Molecular Medicine at The George Washington University School of Medicine and Health Sciences in Washington, DC as well as the mother of a son with an autism spectrum disorder (ASD).  Dr. Hu was trained as a chemist, with a Ph.D. in Chemistry from the California Institute of Technology and a B.S. in Chemistry from the University of Hawaii. She has a long research history in cross-disciplinary studies focused on protein structure-function relationships and membrane-protein interactions.  In late 2004, because of her personal interest in ASD, she redirected her research focus towards autism. Dr. Hu has since become a leader in the application of multi-disciplinary, integrative genomics approaches to ASD which involve the integration of large-scale data from gene expression, behavioral, genetic, and epigenetic analyses.  Currently, she has turned her attention to environmental contributors that may increase risk for autism through alterations of the epigenome that may be responsible at least in part for the heritability of autistic traits.

Grants

Ongoing:
Title: Impact of endocrine disruptors on the human sperm methylome: a risk factor for autism?
Source: NIEHS Project Period: 10/15/17 – 9/30/19
Role: P.I.
Hypotheses: This study is designed to test the hypotheses that: 1) environmental exposure to endocrine disrupting compounds (EDCs), especially organochlorines with long half-lives in the environment and bodily tissues, is associated with epigenetic modifications in human sperm cells, and 2) the expression and epigenetic regulation of genes mapped to differentially methylated regions (DMRs) are altered by the specific EDCs in a neuronal cell model.
Specific Aims: 1) identify differentially methylated regions (DMRs) as a function of exposure to specific endocrine disruptors, specifically, DDE; 2) investigate effect of DDE on gene expression in a neuronal cell model.
Impact: Knowledge gained from these studies is expected to fill a gap in our knowledge of environmentally-induced epigenetic changes in human germline cells that may increase risk for autism. Aside from potentially influencing autism phenotype in children of the directly exposed fathers, epigenetic modifications in sperm may also be transmitted across generations, with such changes potentially contributing to the “missing heritability” in autism.


Recently Completed Research Support:
Title: Are endocrine disrupting compounds an environmental risk factor for autism?
Source: NIEHS Project Period: 4/15/14 -3/31/16 with NCE to 3/31/18
Role: P.I.
The goal of this project is to develop a rapid screening method to assay the potential of a wide variety of endocrine disrupting compounds (EDC) to disrupt the expression level of RORA, a functionally relevant candidate gene for autism, whose dysregulation may be a biomarker for elevated risk for autism. This elevated risk is suggested by our recent study which showed that RORA potentially regulates over 2500 other genes, including over 400 other autism candidate genes. We have also validated six of these gene targets and demonstrated the reduced expression of these genes in RORA-deficient postmortem brain tissues from individuals with autism. This study will also investigate epigenetic mechanisms associated with the EDC-induced dysregulation of RORA.
 
The long-term objectives of our laboratory are to identify specific gene-environment interactions that may increase risk for ASD and to understand their mechanisms of action.
Specific Aims of this project:
1)   Investigate the impact of a broad class of endocrine disrupting compounds (EDCs) on RORA expression;
2)   Investigate epigenetic modifications associated with EDC-mediated alteration of RORA expression as a mechanism for G x E interactions that may have transgenerational consequences.

Awards

Emily Cavaliere Puzio and Frank Mauro Puzio Fellows Award 2013; Princeton Lecture Series “given as a tribute to your contributions to the field of autism research”, March 22, 2013.
Member of: Sigma Xi, Phi Beta Kappa, Phi Kappa Phi, Alpha Lambda Delta

Teaching

Courses taught (cumulative since 1989) Departmental
Bioc 6234:Structure and function of proteins
(1989-2015)
Physical properties shaping proteins
Protein folding
Protein-protein interactions
Membrane proteins
Principles and applications of fluorescence
Nuclear magnetic resonance of proteins
Bioinformatic approaches to protein structure analysis
Bioc 6221 General Biochemistry (1989 – present) Membranes
Membrane transport mechanisms
Cytoskeleton
Cell cycle
Protein modifications
Protein trafficking
Protein folding
Protein engineering
From sequence to function
Bioc 6222 (2018-pres.) lncRNA in neurodevelopmental disorders
Bioc 6266 Medical Genomics (2014-pres.) Genomics/epigenetics of autism (2-3 lectures)
Bioc 6240 (2018) Gene ontology and pathway analysis
Bioc 6236 Fundamentals of Genomics (2005 – pres.) cDNA microarrays: Protocols and experimental
DNA microarray data analysis and interpretation Integrative genomics approach to autism
Bioc 239 Applied Bioinformatics Commercial pathway analysis software for the interpretation of microarray data
Bioc 223 Biochemical Techniques Fluorescence, Nuclear magnetic resonance
Bioc 211 Biochemistry for Health Sciences Students Amino acids/Proteins
Protein Structure/Function/Enzymes
Isoenzymes, Coenzymes, Vitamins
Bioc 227 Biochemistry Seminar (Director) Seminars by and for graduate students
Bioc 252 Biochemical and Molecular Aspects of Selected Diseases p53
Bioc 254 Fundamentals of Molecular Biology Epigenetics: Concepts and Methods
Cells & Tissues Cell cycle regulation Intercellular junctions – structure & function
IBS (Ph.D. program) and Other Departments  
BMSC 213 Molecular Medicine Autism spectrum disorders
BMSC 212 Cell Biology (Course director, 2002-2004, 2006) Origin of cells/cell culture techniques
Intercellular junctions
BMSC 210 Proteins Membranes
Membrane transport mechanisms
BMSC 211 Nucleic acids and Information Processing Cell cycle
Gnet 201 Advanced Problems in Genetics Molec. & Cell. Response to Radiation
Micro 229 Immunology Complement proteins and receptors Molec. & Cell. Response to Radiation
Other Departments  
Speech and Hearing Sciences Autism
Graduate School of Education and Human
Development (2 different graduate courses)
Autism: Genomic studies
School of Public Health and Health Services
Course: Molecular Epidemiology
Epigenetic mechanisms

Research

Our laboratory’s long-term goals are the molecular diagnosis and personalized treatment of autism spectrum disorders (ASD) which are pervasive neurodevelopmental disorders now affecting nearly one in 58 individuals in the US.  To accomplish these goals, the laboratory is employing integrative genomics and systems biology approaches, coupled with measures that reduce the clinical and symptomatic heterogeneity among cases, in order to develop a better understanding of the biological bases of ASD through the identification of ASD-impacted genes, pathways, and gene regulatory mechanisms specific to the different subtypes of ASD.  This strategy has led to the discovery of novel candidate genes relevant to the pathobiology of ASD as well as to the identification of potential diagnostic biomarkers at multiple levels: gene expression, microRNA, DNA methylation, and genetics. Ongoing and planned studies are directed towards further identification of subtype-specific dysregulated genes and pathways for targeted therapeutics as well as environmental factors influencing risk for ASD.  The “Autism Pyramid” shown below summarizes the different areas of research undertaken by our laboratory.

ASD Research Pyramid
The Autism Pyramid Schematic summarizes published and ongoing studies from Dr. Hu’s laboratory which are designed to investigate the various factors contributing to risk for autism. [Numbers on the pyramid schematic refer to numbered articles below. See Reviews for more comprehensive discussion of these factors.]
 
ASD Phenotypes

1. 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 2:67-77.  [This paper introduces a novel way to divide individuals with ASD into more homogeneous subtypes that are more amenable to gene expression, genetics, and other biological analyses.]
 
Gene Expression Profiling
2. 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.  [This was the first study to demonstrate differences in gene expression between individuals (discordantly diagnosed monozygotic twins) based upon diagnosis of autism.]
 
3. Hu, V.W., Nguyen, A., Kim, K.S., Steinberg, M.E., Sarachana, T., Scully, M., 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 4(6): e5775.  [This paper revealed the potential role of steroid hormone metabolism in autism.]

4. Hu, V.W., Sarachana, T., Kim, K.S., Nguyen, A., Kulkarni, S., 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 2:78-97.  [This paper demonstrates the importance of phenotyping ASD in revealing meaningful biological differences between subgroups of individuals with ASD, which may be translated to targeted therapies.]
 
Genetics
5. Hu, V.W., Addington, A., and Hyman, A. (2011) Novel Autism Subtype-dependent Genetic Variants are Revealed by Quantitative Trait and Subphenotype Association Analyses of Published GWAS Data.  PLoS ONE Apr 27; 6(4):e19067. [This study demonstrates that dividing individuals with ASD by subtypes (using ADIR severity scores as described for gene expression profiling) significantly improves the ability to identify novel subtype-dependent genetic variants or SNPs that may be useful for diagnosis.]
 
6. Talebizadeh, Z., Arking, D.E., and Hu, V.W. (2013) A novel stratification method in linkage studies to address inter and intra family heterogeneity in autism.  PLoS ONE, 8(6):e67569.  [This linkage study revealed both inter- and intra-family genetic heterogeneity in ASD.]
 
Epigenetics
7. 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., 24(8):3036-51.  [This was the first publication on the investigation of global methylation differences in ASD.  By integrating the methylation data with expression data from the same samples, we identified several novel ASD candidate genes, including RORA, which have led to new insight on gene x environment interactions involving the sex hormones.]

8. 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, (4):23.

Triggers: Gene x Environment Interactions
9. Sarachana, T., Xu, M., Wu, R.-C., and Hu, V.W. (2011) Sex hormones in autism: Androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism PLoS ONE, 6(2): e17116.  [The significance of these findings with respect to the sex bias in ASD was reviewed in Scientific American Mind, Jul. 2011.]

10. Hu, V.W. (2012) Is retinoic acid-related orphan receptor-alpha (RORA) a target for gene-environment interactions contributing to autism? Neurotoxicology, 33:1434-1435. 

11. Sarachana, T. and Hu, V.W. (2013) Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder.  Molecular Autism, 4:14. doi:10.1186/2040-2392-4-14. 

12. Sarachana, T. and Hu, V.W. (2013) Differential recruitment of coregulators to the   RORA promoter adds another layer of complexity to gene (dys)regulation by sex hormones in autism.  Molecular Autism, 4:39. 

13. Hu, V.W., Sarachana, T., Sherrard, R.M., and Kocher, K.M. (2015) Investigation of sex            differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism. Molecular Autism, 6:7.

14. Moosa, A., Shu, H., Sarachana, T., and Hu, V.W. (2017) Are endocrine disrupting compounds environmental risk factors for autism spectrum disorder? Hormones and Behavior, 101:113-21. 

Ongoing studies:  We are currently investigating the effects of environmentally ubiquitous endocrine disrupting chemicals on the epigenome in sperm cells to assess the potential of this class of environmental pollutants to alter the regulation of genes associated with autism.
 
ASD Biomarkers
15. Hu, V.W. and Lai, Y. (2013) Developing a predictive gene classifier for autism spectrum            disorders based upon differential gene expression profiles of phenotypic subgroups. North American Journal of Medicine and Science, 6(3):107-116.

16. Hu, V.W. (2012) Subphenotype-dependent disease markers for Diagnosis and Personalized Treatment of Autism Spectrum Disorders. Disease Markers, 33:2-288. 

Reviews: Integrated genomics and a systems approach to autism
17. Hu, V.W. (2011) A systems approach towards an understanding, diagnosis and personalized treatment of autism spectrum disorders.  Pharmacogenomics 12(9):1235-8.
 
18. Hu, V.W. (2013) From Genes to Environment:  Using integrative genomics to build a “systems level” understanding of autism spectrum disorders.  Child Development 84(1):89-103. 

19. Hu, V.W. (2013) The Expanding Genomic Landscape of Autism: Discovering the “Forest” Beyond the “Trees”. Future Neurology, 8(1):29-42.

Additional publications are accessible through ORCID: < http://orcid.org/0000-0002-3357-0777>
 
Book
Frontiers in Autism Research: New Horizons for Diagnosis and Treatment,   V.W. Hu, Ed., World Scientific, New Jersey, London, Singapore; May 2014.
      This unique book (26 chapters) focuses on the emerging and expanding areas of research on autism spectrum disorders (ASD). These areas include investigations of genome-wide genetics and epigenetic contributions, metabolic and immune dysfunction, gene-environment interactions, as well as the role of alternative splicing, RNA editing, and noncoding RNAs in gene regulation.  Novel therapies including rational biology-based pharmacotherapies, transcranial magnetic stimulation, art and music therapy are also discussed.
 
Video   <https://www.youtube.com/watch?v=6sYRYzsS45Y>
The video at the URL given above presents an interview with Dr. Valerie Hu which discusses the integrative genomics approach her laboratory is taking towards understanding the biological bases of ASD, with a focus on the underlying genes and pathways associated with subphenotypes of ASD which may be useful as subtype-specific therapeutic targets.
  
Patent awarded: Patent No.: US 8,962,307 B2; Feb. 24, 2015
Title: Method and Kit for Diagnosing Autism using Gene Expression Profiling
Role: Valerie W. Hu, Inventor
The subject of this patent is the development of a diagnostic gene panel for ASD based upon differential gene expression between individuals with ASD and neurotypical controls, using peripheral tissues for diagnostic samples.
 

Centers and Institutes

GW Institute for Biomedical Sciences

GW Autism and Neurodevelopmental Disorders Institute

GW Neuroscience Institute

Publications

View publications by this faculty member from January 1, 2013 - present

Hu, V.W. (2013) From Genes to Environment: Using integrative genomics to build a “systems level” understanding of autism. Invited review, Child Development, 84(1):89-103. PMID: 22497667

Hu, V.W. (2013) The Expanding Genomic Landscape of Autism Spectrum Disorders: Discovering the “Forest” Beyond the “Trees”, Invited perspective article, Future Neurology, 8(1):29-42.

Sarachana, T. and Hu, V.W. (2013) Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder. Molecular Autism, 4(1):14. PMID: 23697635

Talebizadeh, Z., Arking, D.E., and Hu, V.W. (2013) A novel stratification method in linkage studies to address inter and intra family heterogeneity in autism. PLoS ONE, 8(6):e67569.

Hu, V.W. and Lai, Y. (2013) Developing a predictive gene classifier for autism spectrum disorders based upon differential gene expression profiles of phenotypic subgroups. North American Journal of Medicine and Science, 6(3):107-116. Download PDF

Sarachara, T. and Hu, V.W. (2013) Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys)regulation by sex hormones in autism. Molecular Autism, in press.

Hu, V.W. (2012) Is retinoic acid-related orphan receptor-alpha (RORA) a target for gene-environment interactions contributing to autism? Neurotoxicology, 33(6):1434-35. PMID: 22967355

Hu, V.W. (2012) Subphenotype-dependent disease markers for diagnosis and personalized treatment of autism spectrum disorders. Invited Review, Disease Markers, 33(5):277-88. PMID: 22960334 Download PDF

Sarachana, T., Xu, M., Wu, R.-C., and Hu, V.W. (2011) Sex hormones in autism: Androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism PLoS ONE, 6(2): e17116. PMID: 21359227

Hu, V.W., Addington, A., and Hyman, A. (2011) Novel Autism Subtype-dependent Genetic Variants are Revealed by Quantitative Trait and Subphenotype Association Analyses of Published GWAS Data PLoS ONE 6(4):e19067. PMID: 21556359

Hu, V.W. (2011) A Systems Approach towards an Understanding, Diagnosis, and Personalized Treatment of Autism Spectrum Disorders. Invited editorial, Pharmacogenomics, 12(9):1235-38. PMID: 21919600

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., 24(8):3036-51. PMID: 20375269

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, 2(4):23 PMID: 20374639

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 2:67-77. PMID: 19418574; PMCID: PMC2737479

Hu, V.W., Sarachana, T., Kim, K.S., Nguyen, A., Kulkarni, S., 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 2:78-97. PMID: 19455643; PMCID: PMC2737477

Hu, V.W., Nguyen, A., Kim, K.S., Steinberg, M.E., Sarachana, T., Scully, M., 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 4(6): e5775. PMID: 19492049; PMCID: PMC2685981

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. PMID: 16709250

Additional publications published before January 1, 2013 may be available within Himmelfarb Library's database.

Industry Relationships and Collaborations

This faculty member (or a member of their immediate family) has reported a financial interest with the healthcare related companies listed below. These relations have been reported to the University and, when appropriate, management plans are in place to address potential conflicts.

  • None