G. Wesley HatfieldProfessor, Institute for Genomics and Bioinformatics Professor, Chemical Engineering & Materials Science Associate Director, UCI Institute for Genomics and Bioinformatics (IGB) Director, IGB Computational Biology Research Laboratory (CBRL) Chief Scientist and Founder, CODA Genomics, Inc. (Laguna Hills, CA) |
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Research Interests |
Molecular mechanisms of biological control systems; global gene expression; genomics; bioinformatics; computational biology | |
| URL | www.ucihs.uci.edu/microbio/facultyResearch/faculty/hatfield.html | |
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Academic Distinctions |
Purdue University Alumnus of the Year Award, 2007 UCI 40th Anniversary Faculty Innovation and Entrepreneurship Award, 2005 UCI Athalie Clark Outstanding Researcher Award, 1999 Elected Fellow of the Academy of Microbiology, 1993 IPA Visiting Scientist Award, National Cancer Institute, 1980 American Society of Microbiology Eli Lilly Research Award, l975 National Institutes of Health Career Development Award, l97l-77 National Institutes of Health Postdoctoral Fellowship Award l968-70 National Institutes of Health Predoctoral Fellow Award, l964-68 Appointments: Assistant Professor, Medical Microbiology, College of Medicine, University of California, Irvine, l970-72. Associate Professor, Medical Microbiology, College of Medicine, University of California, Irvine, l973-76. Professor, Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, l977 to present. Professor,Chemical Engineering and Materials Science, Samueli School of Engineering, University of California, Irvine, l994 to present. Co-Director, UCI Institute for Genomics and Bioinformatics, 2000 to present. Director, IGB Computational Biology Laboratory, Cal(IT)2. 2004 - present |
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| Appointments |
Assistant Professor of Medical Microbiology, College of Medicine, University of California, Irvine, l970-72. Associate Professor of Medical Microbiology, College of Medicine, University of California, Irvine, l973-76. Professor of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, l977 to present. Professor of Chemical Engineering and Materials Science, Samueli School of Engineering, University of California, Irvine, l994 to present. |
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Research Abstract |
Researchers in the Hatfield laboratory employ computational and modern genomic methods to study global gene regulation and mechanisms of pathogenesis in the model organism Escherichia coli K12 and pathogenic bacteria. Effects of Chromosome Structure and Topology on Gene Expression - Dr. Hatfield and his colleagues were the first to demonstrate that superhelical energy is stored at many supercoiling-induced DNA duplex destabilized (SIDD) sites around the chromosome, and that DNA architectural proteins such as the IHF protein can alter the structure of the chromosome in ways that redistribute this energy among SIDD sites to lower the energy of activation for biochemical reactions that require DNA strand separation such as DNA replication, recombination, and transcription initiation. They have further demonstrated that DNA topology-dependent mechanisms are involved in the coordination of basal level expression of the operons of the ilv regulon of the bacterium Escherichia coli with one another and the with the growth conditions of the cell (Sheridan, Benham, and Hatfield, 1998; Sheridan, Benham, and Hatfield, 1999; Rhee et al., 1999; Opel and Hatfield, 2000; Opel and Hatfield, 2001; Opel et al. 2001; Sheridan et al. 2001). This work has provided a new paradigm to study the effects of chromosome structure on global patterns of gene expression. Functional Genomics and Bioinformatics - Researchers in the Hatfield lab are using computational and genomic methods to further define DNA topology-dependent regulatory mechanisms responsible for coordinating the expression of large families of genes with the environmental and nutritional growth conditions of the cell. It has been known for some time that the global superhelical density of the chromosome varies over a wide range in response to various types of environmental assaults such as osmotic, temperature, and anaerobic shocks and nutritional upshifts and downshifts. Published results from the Hatfield lab have shown that the effect of DNA supercoiling-dependent mechanisms on the expression of the operons of the ilv regulon is to coordinate basal level expression of these operons (independent of operon-specific controls) in response to changes in the global superhelical density of the bacterial chromosome to coordinate the capacity for branched chain amino acid biosynthesis with the environmental and nutritional growth conditions of the cell. To determine if this represents a general control mechanism for coordinating the expression of other genes (operons) requires knowledge of the location and thermodynamic stability of each of the SIDD sites on the E. coli chromosome at different physiological superhelical densities encountered under different growth conditions. This information, together with the location and in vivo occupancy of each of the high affinity IHF sites on the E. coli chromosome and the effects of IHF on global gene expression profiles under these same conditions will facilitate an assessment of the generality of this mechanism. To this end, Hatfield and his collaborator, Craig J. Benham at UC Davis, have recently completed calculations of the Gibbs free energy of destabilization of each base pair in the E.coli chromosome, and the location and thermodynamic stability of all of the SIDD sites at a mid physiological chromosomal superhelical density. Calculations at the global chromosomal superhelical densities encountered under different environmental and nutritional growth conditions are in progress. Hatfield and his research group also are developing novel genomic SELEX methods to isolate in vivo cross-linked IHF protein-chromosomal DNA fragments for hybridization to DNA arrays containing probes for all of the E. coli inter-ORF (upstream regulatory) regions to identify all of the chromosomal IHF-binding sites and their relative occupancies on the E. coli chromosome. Thus, together with future knowledge of the location and in vivo occupancy of IHF at its high affinity chromosomal binding sites and the location and stability of the SIDD sites around the E coli chromosome in wild-type and IHF- strains grown under different environmental and nutritional conditions, these data will allow Hatfield and his colleagues to assess the generality of global gene regulation by IHF-mediated translocation of superhelical energy from one site on the chromosome to another. DNA Microarrays - In pursuit of these goals, the Hatfield group has used pre-synthesized nylon membranes spotted in duplicate with full-length PCR-generated products of each of the 4,290 predicted E. coli K12 ORFs and in situ synthesized Affymetric GeneChips to measure the gene expression profiles in otherwise isogenic IHF+ and IHF- strains (Arfin et al., 2000). To evaluate the data generated by these gene expression profiling experiments, they developed (in collaboration with A.D. Long of the Ecology and Evolution Department and P. Baldi of the Infomation and Computer Sciences Department) a novel linear Analysis of Variance (ANOVA) model appropriate for the analysis and interpretation of DNA microarray data (Long et al., 2001). These statistical methods allow them to identify and minimize experimental variables that affect the reproducibility and accuracy of DNA microarray measurements, and to determine the statistical significance of observed differences between expression levels of each ORF in these two genotypes. These statistical tools required for the analysis of DNA microarray data have been incorporated into a computer program called Cyber-T. Cyber-T is available for online use at the UCI Functional Genomics web site, www.genomics.uci.edu. Other software for the processing and analysis of genomic data developed in collaboration with members of the Hatfield laboratory include: MERGEM, a utility for merging large data sets; and, GAP Finder, a program to design complete genome primer sets for ORFs or inter-ORFs for the manufacture of PCR-based DNA microarrays. These programs are also available for online use at the UCI genomics web site. Dr. Hatfield is the coordinator of the Biomedical Informatics training track of the UCI combined graduate training program in Molecular Biology, Genetics and Biochemistry. The UCI Computational Biology Research Laboratory- Many research programs at UCI and around the world would be advanced by the ability to produce a synthetic gene rapidly that encodes a protein of interest and is optimized for desirable sequence properties, such as optimal translation kinetics for folding and expression in a chosen target organism. However, since most genes are hundreds to thousands of nucleotides long and it is not possible accurately to synthesize DNA molecules longer than fifty to eighty nucleotides, the rapid synthesis of tailored genes has not been possible. Now, Rick Lathrop of the UCI School of Information and Computer Science, and Wes Hatfield of the Department of Microbiology and Molecular Genetics in the UCI College of Medicine, have developed and secured UC patent protection on methods to accomplish this very task. This method involves the computational optimization of DNA sequences to allow the correct self-assembly of many overlapping short synthetic DNA oligonucleotides into a complete gene of any desired nucleic acid or amino acid sequence. More specifically, scores of short overlapping synthetic nucleotides, each around fifty nucleotides long, are designed so that complementary, overlapping, regions on alternating strands will hybridize with great efficiency at a high temperature that precludes all nonproductive hybridization events. The thermal stability of these self-assembled genes allows them to be hybridized into any plasmid expression vector and transformed into cells, or used directly as DNA templates to produce proteins in coupled in vitro transcription-translation systems. Since this method is rapid (no more than a few hours) and demands no more than mixing, heating, and cooling, computationally designed oligonucleotides in solution with no purification steps, it is imminently suited for automation for such applications as rapidly producing the entire proteomes or genomes of organisms. Online access to this computationally optimized DNA assembly technology is currently available to UCI faculty through the services of the UCI Computational Biology Research (CBR) Laboratory DIrected by Dr. Hatfield and Dr. Rick Lathrop of ICS. In addition to his position as the Associate Director of the Institute for Genomics and Bioinformatics, Dr. Hatfield is the coordinator of the Biomedical Informatics training track of the UCI combined graduate training program in Molecular Biology, Genetics and Biochemistry (MBGB), and the co-director of the NIH-funded UCI Bioinformatics Training (BIT) Program for predoctoral and postdctoral trainees. Patents: 1. G.W. Hatfield. Conversion of methanol to hydrogen peroxide; U.S. Patent #4,920,055; Filed 2/4/85, Issued 4/24/90. 2. G.W. Hatfield and G. A. Gutman. Non-random utilitzation of codon pairs in Escherichia coli; U.S. Patent #5,082,767; filed 2/27/89, Issued 1/21/92. 3. G. W. Hatfield and D. A. Hoiberg Enzymatic process for manufacturing formaldehyde and hydrogen peroxide; U.S. Patent #5,234,827; Filed 5/8/87, Issued 8/10/93. 4. D. A. Hoiberg, G. W. Hatfield, H. S. Moyed, and J. A. Sharp. Conversion of alcohols to aldehydes and hydrogen peroxide by substrate and product tolerant methanol oxidases. U.S. Patent #5,266,487; Filed 10/6/92, Issued 11/30/93. 5. R. L. Lathrop and G. Wesley HatfieldPending U.S. Patent Application entitled " METHOD FOR PRODUCING A SYNTHETIC GENE OR OTHER DNA SEQUENCE”, filed 05/21/2004, assigned to The Regents (UC Case No. 2002-328-2); Allowed April 2007. 6. R. L. Lathrop and G. Wesley HatfieldP. ending U.S. Patent Application entitled “A SIMPLE METHOD OF SYNTHETIC GENE ASSEMBLY FROM POOLS OF OLIGONUCLEOTIDES”, filed 03/31/05, and assigned to The Regents (UC Case No. by 2005-447-1); |
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| Publications | BOOK | |
| Pierre Baldi and G. Wesley Hatfield, (2002) "DNA Microarrays and Gene Expression: From Experiments to Data Analysis and Modeling". Cambridge University Press.214 pp. ISBN: 0521800226 | ||
| Go to Dr. Hatfield's website link below to view all of his PUBMED publications. | ||
| Grant | Current Extramural Grant Awards: 1) Source of support: NIH GM68903 Total award amount (direct costs): $1,000,000 Total Award Period Cover: 9/19/03 – 8/31/07 Proposal title: Global Regulatory Networks in Escherichia. coli. Principal Investigator: G. Wesley Hatfield 2) Source of support: NSF ITR44603121784 Total award amount (direct costs): $1,500,000 Total Award Period Covered: 9/1/02 – 8/31/07 Proposal title: "Information Technology for the Self-assembly of Synthetic Genes" Co-principal Investigators: Richard L. Lathrop and G. Wesley Hatfield 3) Source of support: NIH Training Grant LM07443 Total award amount (direct costs): $5,470,204 Total Award Period Covered: 7/31/07 – 6/30/12 Proposal title: "Biomedical informatics training (BIT) program Co-Directors: Pierre Baldi and G. Wesley Hatfield 4) Source of support: UC Discovert Grant Total award amount (direct costs): $2,000,484 Total Award Period Covered: 7/31/07 – 6/30/09 Proposal title: Computationally Optimized Metabolic Pathways for Biofuels Production PI: G. Wesley Hatfield | |
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Professional Societies |
Federation of American Societies for Experimental Biology International Society for Computational Biology |
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| Graduate Programs |
Biomedical Engineering |
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| Research Center | Institute for Genomics and Bionformatics | |
| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=2473 | |
| Last updated | 06/05/2007 | |