Professor Colin Smith
Professor of Functional Genomics
Qualifications: B.Sc, PhD
Phone: Work: 01483 68 6937
Room no: 15 AX 02
0900-1700 h, Monday-Friday
My first degree, in Microbiology, was obtained from the University of Bristol in 1981.
From 1981-1984 I undertook my PhD studies on molecular genetics of Streptomyces in the labs of Prof Keith Chater and Prof Sir David Hopwood at the John Innes Institute, Norwich. My research was focussed on developing RNA methods for Streptomyces and characterisation of gene structure and regulation - using the glycerol catabolic operon as a model system.
I moved back to the University of Bristol (Biochemistry Department) in 1985 to work as a postdoctoral research associate in the lab of Professor Nigel Brown, continuing to dissect regulatory mechanisms controlling the glycerol operon. I took up a Lectureship in Molecular Genetics at UMIST (Manchester) in 1988 and for the next 10 years studied a range of regulatory systems in Streptomyces, most notably the heat-shock response.
From 1999 I started to embrace multidisciplinarity - engaging in collaborative research projects with chemists, mathematicians, engineers, statisticians and computer scientists. From 2001-2002 I undertook a sabbatical in the Control Systems Centre (Dept. Electronics and Electrical Engineering) at UMIST with Dr Olaf Wolkenhauer. Since then my major research areas have been biosynthetic engineering on nonribosomal peptide antibiotics, DNA microarray technology, global analysis of gene expression and characterization of transcriptional regulatory networks.
For the last 10 years I have managed a BBSRC/EC funded microarray/bioinformatics resource at Surrey (formerly at Manchester), principally for the international Streptomyces community. I moved to the University of Surrey in 2003 to take up the new Chair of Functional Genomics, My major areas of research currently revolve around systems level analysis of Streptomyces regulatory networks and of human sleep physiology in the context of global gene expression (monitored from leukocytes).
A. Systems biology of Streptomyces coelicolor
Our current activities cover two broad inter-related areas:
1. Transcriptional regulatory networks controlling morphological and ‘physiological’ differentiation (e.g. antibiotic production). We are in the process of constructing transcription factor regulatory networks by using a combination of global gene expression profiling and ChIP-on-chip analysis approaches. We have developed experimentally-validated high density arrays (44,000 x 60 mer and 105,000 x 60 mer formats) for this work. In addition to examining the global distribution of RNA polymerase we are currently investigating several transcription factors, including PhoP, CdaR, AbsA2 and DasR (in collaboration with Gilles van Wezel at Leiden University, NL) and AtrA (in collaboration with Kenny McDowall at Leeds University, UK).
2. Non-coding RNA and the primary transcriptome of Streptomyces coelicolor. In recent years it has become clear that small non-coding RNAs play a diverse role in the control of cellular processes in bacteria. We have used our 105K arrays to identify large numbers of small intergenic non coding RNAs, some of which are implicated in controlling morphology and antibiotic production. We are now switching to applying ‘RNA-seq’ to build a comprehensive picture of all non-coding RNAs under a variety of liquid and surface-grown conditions. It is envisaged that the findings of this study will be integrated with the data on transcription factor regulatory networks and that both will ultimately be integrated with the genome scale metabolic network.
External: Gilles van Wezel (Leiden), David Hodgson (Warwick), Mark Paget (Sussex), Klas Flärdh (Lund) and Kenny McDowall
Current funding from the BBSRC
On-line research resources
We have developed a number of on-line tools for microarray data analysis, genomics and metabolic pathway analysis. Microarrays and a variety of software tools and data resources are available from our website.
B. Systems level analysis of human sleep physiology
The generic nature of high throughput techniques such as gene expression profiling has led us to develop multidisciplinary collaborations with other groups within FHMS. We are working with Prof Derk-Jan Dijk and others in the Surrey Sleep Research Centre on two major inter-related research contracts:
1. Circadian and homeostatic contributions to physiology, cognition and
genome-wide expression in human and mouse variants of the PER3 VNTR
polymorphism [BBSRC funded since 2008]
2. Cognitive vulnerability following extended wakefulness in defined genotypes:
Effects of sleep duration on sustained attention, executive function, and
novel biomarkers [AFOSR (USA) funded since 2008].
C. Global analysis of gene expression in tumours following chemotherapy. Collaboration with Professor N. Karanjia (Royal Surrey County Hospital), supported by the Liver Cancer Surgery Appeal since 2007.
D. Vitamin D fortification, vitamin D status and global gene expression in leukocytes
A new BBSRC-funded collaboration with Drs Sue Lanham-New and Kath Hart within FHMS: Ergocalciferol (D2) vs. Cholecalciferol (D3) Food Fortification: Comparative Efficiency in Raising 25OHD Status & Mechanisms of Action (D2-D3 Study) [Funded from 2011]
- 'Deciphering the Regulon of Streptomyces coelicolor AbrC3, a Positive Response Regulator of Antibiotic Production.'. Appl Environ Microbiol, United States: 80 (8), pp. 2417-2428.doi: 10.1128/AEM.03378-13
- 'Mistimed sleep disrupts circadian regulation of the human transcriptome.'. Proc Natl Acad Sci U S A, United States: 111 (6), pp. E682-E691. . (2014)
- 'Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome.'. Proc Natl Acad Sci U S A, United States: 110 (12), pp. E1132-E1141. . (2013)
- 'The ROK-family regulator Rok7B7 pleiotropicaly affects xylose utilization, carbon catabolite repression and antibiotic production in Streptomyces coelicolor.'. American Society for Microbiology J Bacteriol, 195 (6), pp. 1236-1248.doi: 10.1128/JB.02191-12Full text is available at: http://epubs.surrey.ac.uk/803533/
Members of the ROK family of proteins are mostly transcriptional regulators and kinases that generally relate to the control of primary metabolism, whereby its member glucose kinase acts as the central control protein in carbon control in Streptomyces. Here we show that deletion of SCO6008 (rok7B7) strongly affects carbon catabolite repression (CCR), growth and antibiotic production in Streptomyces coelicolor. Deletion of SCO7543 also affected antibiotic production, while no major changes were observed after deletion of the rok family genes SCO0794, SCO1060, SCO2846, SCO6566 or SCO6600. Global expression profiling of the rok7B7 mutant by proteomics and microarray analysis revealed strong up-regulation of the xylose transporter operon xylFGH, which lies immediately downstream of rok7B7, consistent with the improved growth and delayed development of the mutant on xylose. The enhanced CCR, which was especially obvious on rich or xylose-containing media, correlated with elevated expression of glucose kinase and of the glucose transporter GlcP. In liquid-grown cultures, expression of the biosynthetic enzymes for production of prodigionines (Red), siderophores and calcium dependent antibiotic (Cda) was enhanced in the mutant, and overproduction of Red was corroborated by MALDI-ToF analysis. These data present Rok7B7 as a pleiotropic regulator of growth, CCR and antibiotic production in Streptomyces.
- 'Identification of new developmentally regulated genes involved in Streptomyces coelicolor sporulation.'. BMC Microbiol, England: 13 . (2013)
- 'Reconstructing regulatory networks in Streptomyces using evolutionary algorithms'. 2013 13th UK Workshop on Computational Intelligence, UKCI 2013, , pp. 24-30. . (2013)
- 'Diverse control of metabolism and other cellular processes in Streptomyces coelicolor by the PhoP transcription factor: genome-wide identification of in vivo targets.'. Oxford University Press Nucleic Acids Res, doi: 10.1093/nar/gks766Full text is available at: http://epubs.surrey.ac.uk/725768/
Streptomycetes sense and respond to the stress of phosphate starvation via the two-component PhoR-PhoP signal transduction system. To identify the in vivo targets of PhoP we have undertaken a chromatin-immunoprecipitation-on-microarray analysis of wild-type and phoP mutant cultures and, in parallel, have quantified their transcriptomes. Most (ca. 80%) of the previously in vitro characterized PhoP targets were identified in this study among several hundred other putative novel PhoP targets. In addition to activating genes for phosphate scavenging systems PhoP was shown to target two gene clusters for cell wall/extracellular polymer biosynthesis. Furthermore PhoP was found to repress an unprecedented range of pathways upon entering phosphate limitation including nitrogen assimilation, oxidative phosphorylation, nucleotide biosynthesis and glycogen catabolism. Moreover, PhoP was shown to target many key genes involved in antibiotic production and morphological differentiation, including afsS, atrA, bldA, bldC, bldD, bldK, bldM, cdaR, cdgA, cdgB and scbR-scbA. Intriguingly, in the PhoP-dependent cpk polyketide gene cluster, PhoP accumulates substantially at three specific sites within the giant polyketide synthase-encoding genes. This study suggests that, following phosphate limitation, Streptomyces coelicolor PhoP functions as a 'master' regulator, suppressing central metabolism, secondary metabolism and developmental pathways until sufficient phosphate is salvaged to support further growth and, ultimately, morphological development.
- 'Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis.'. American Society for Nutrition Am J Clin Nutr, United States: 95 (6), pp. 1357-1364.Full text is available at: http://epubs.surrey.ac.uk/725769/
Currently, there is a lack of clarity in the literature as to whether there is a definitive difference between the effects of vitamins D(2) and D(3) in the raising of serum 25-hydroxyvitamin D [25(OH)D].
- 'Introduction of a Non-Natural Amino Acid into a Nonribosomal Peptide Antibiotic by Modification of Adenylation Domain Specificity'. WILEY-V C H VERLAG GMBH ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 51 (29), pp. 7181-7184. . (2012)
- 'Genome-wide transcriptomic analysis of the response to nitrogen limitation in Streptomyces coelicolor A3(2).'. BMC Res Notes, England: 4Full text is available at: http://epubs.surrey.ac.uk/203297/
- 'Active site modification of the beta-ketoacyl-ACP synthase FabF3 of Streptomyces coelicolor affects the fatty acid chain length of the CDA lipopeptides'. ROYAL SOC CHEMISTRY CHEMICAL COMMUNICATIONS, 47 (6), pp. 1860-1862.doi: 10.1039/c0cc03444d
- 'RankProdIt: A web-interactive Rank Products analysis tool.'. BMC Res Notes, England: 3Full text is available at: http://epubs.surrey.ac.uk/203303/
- 'Metabolic and evolutionary insights into the closely-related species Streptomyces coelicolor and Streptomyces lividans deduced from high-resolution comparative genomic hybridization.'. BMC Genomics, England: 11Full text is available at: http://epubs.surrey.ac.uk/203299/
Whilst being closely related to the model actinomycete Streptomyces coelicolor A3(2), S. lividans 66 differs from it in several significant and phenotypically observable ways, including antibiotic production. Previous comparative gene hybridization studies investigating such differences have used low-density (one probe per gene) PCR-based spotted arrays. Here we use new experimentally optimised 104,000 × 60-mer probe arrays to characterize in detail the genomic differences between wild-type S. lividans 66, a derivative industrial strain, TK24, and S. coelicolor M145.
- 'One of the Two Genes Encoding Nucleoid-Associated HU Proteins in Streptomyces coelicolor Is Developmentally Regulated and Specifically Involved in Spore Maturation'. AMER SOC MICROBIOLOGY JOURNAL OF BACTERIOLOGY, 191 (21), pp. 6489-6500.doi: 10.1128/JB.00709-09
- 'A gene expression profiling approach assessing celecoxib in a randomized controlled trial in prostate cancer.'. International Institute of Anticancer Research (IIAR) Cancer Genomics Proteomics, Greece: 6 (2), pp. 93-99.Full text is available at: http://epubs.surrey.ac.uk/203293/
We performed a pilot study, looking at the COX-2 inhibitor celecoxib, on newly diagnosed prostate cancer patients in the neo-adjuvant setting using DNA microarray analysis.
- 'NepA is a structural cell wall protein involved in maintenance of spore dormancy in Streptomyces coelicolor'. WILEY-BLACKWELL PUBLISHING, INC MOLECULAR MICROBIOLOGY, 71 (6), pp. 1591-1603. . (2009)
- 'Development and application of versatile high density microarrays for genome-wide analysis of Streptomyces coelicolor: characterization of the HspR regulon'. BIOMED CENTRAL LTD GENOME BIOLOGY, 10 (1) Article number ARTN R5 Full text is available at: http://epubs.surrey.ac.uk/203295/
- 'Acidic pH shock induces the expressions of a wide range of stress-response genes'. BIOMED CENTRAL LTD BMC GENOMICS, 9 Article number ARTN 604 Full text is available at: http://epubs.surrey.ac.uk/225052/
- 'Antibiotic overproduction in Streptomyces coelicolor A3(2) mediated by phosphofructokinase deletion'. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC JOURNAL OF BIOLOGICAL CHEMISTRY, 283 (37), pp. 25186-25199. . (2008)
- 'Effects of pH shock on the secretion system in Streptomyces coelicolor A3(2)'. KOREAN SOC MICROBIOLOGY & BIOTECHNOLOGY JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY, 18 (4), pp. 658-662. . (2008)
- 'pH shock induces overexpression of regulatory and biosynthetic genes for actinorhodin productionin Streptomyces coelicolor A3(2)'. SPRINGER APPLIED MICROBIOLOGY AND BIOTECHNOLOGY, 76 (5), pp. 1119-1130. . (2007)
- 'Statistical reconstruction of transcription factor activity using Michaelis-Menten kinetics'. BLACKWELL PUBLISHING BIOMETRICS, 63 (3), pp. 816-823. . (2007)
- 'New pleiotropic effects of eliminating a rare tRNA from Streptomyces coelicolor, revealed by combined proteomic and transcriptomic analysis of liquid cultures'. BIOMED CENTRAL LTD BMC GENOMICS, 8 Article number ARTN 261 Full text is available at: http://epubs.surrey.ac.uk/203300/
- 'Loss of the controlled localization of growth stage-specific cell-wall synthesis pleiotropically affects developmental gene expression in an ssgA mutant of Streptomyces coelicolor'. BLACKWELL PUBLISHING MOLECULAR MICROBIOLOGY, 64 (5), pp. 1244-1259. . (2007)
- 'An asparagine oxygenase (AsnO) and a 3-hydroxyasparaginyl phosphotransferase (HasP) are involved in the biosynthesis of calcium-dependent lipopeptide antibiotics'. SOC GENERAL MICROBIOLOGY MICROBIOLOGY-SGM, 153, pp. 768-776.Full text is available at: http://epubs.surrey.ac.uk/225055/
- 'Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains'. Journal of the American Chemical Society, 129 (49), pp. 15182-15192.doi: 10.1021/ja074331o
- 'Analysis of gene expression in operons of Streptomyces coelicolor'. BIOMED CENTRAL LTD GENOME BIOLOGY, 7 (6) Article number ARTN R46 Full text is available at: http://epubs.surrey.ac.uk/203294/
- 'Biosynthesis of the (2S,3R)-3-methyl glutamate residue of nonribosomal lipopeptides'. Journal of the American Chemical Society, 128 (34), pp. 11250-11259.doi: 10.1021/ja062960c
- 'MILVA: An interactive tool for the exploration of multidimensional microarray data'. OXFORD UNIV PRESS BIOINFORMATICS, 21 (22), pp. 4192-4193. . (2005)
- 'SsgA-like proteins determine the fate of peptidoglycan during sporulation of Streptomyces coelicolor'. BLACKWELL PUBLISHING MOLECULAR MICROBIOLOGY, 58 (4), pp. 929-944. . (2005)
- 'A bacterial hormone (the SCB1) directly controls the expression of a pathway-specific regulatory gene in the cryptic type I polyketide biosynthetic gene cluster of Streptomyces coelicolor'. BLACKWELL PUBLISHING LTD MOLECULAR MICROBIOLOGY, 56 (2), pp. 465-479. . (2005)
- 'An experimental evaluation of a loop versus a reference design for two-channel microarrays'. OXFORD UNIV PRESS BIOINFORMATICS, 21 (4), pp. 492-501. . (2005)
- 'Active-site modifications of adenylation domains lead to hydrolysis of upstream nonribosomal peptidyl thioester intermediates'. AMER CHEMICAL SOC JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 126 (16), pp. 5032-5033.doi: 10.1021/ja048778y
- 'Negative feedback regulation of dnaK, clpB and lon expression by the DnaK chaperone machine in Streptomyces coelicolor, identified by transcriptome and in vivo DnaK-depletion analysis'. BLACKWELL PUBLISHING LTD MOLECULAR MICROBIOLOGY, 50 (1), pp. 153-166. . (2003)
- 'Gene expression profiling of human cancers'. NEW YORK ACAD SCIENCES SIGNAL TRANSDUCTION AND COMMUNICATION IN CANCER CELLS, Erice, ITALY: Conference on Signal Transduction and Communication in Cancer Cells 1028, pp. 28-37. . (2004)
Molecular Biology and Genetics – Level 1 (Module co-ordinator)
Molecular Biology and Genetics – Level 2
Molecular Biology and Genetics – Level 3
Microbiology Systems – Level 2
MSc Medical Microbiology (MMIM018) Module: Microbial Genetics and Molecular biology
Faculty Research Strategy Leader for Systems Biology
Academic lead: Core Microarray Facility
Member: Faculty Research Committee
DNA microarray resource
For information on availability of DNA microarrays and their use please access: The Streptomyces coelicolor Microrray Resource