Translational control is a critical type of regulation of gene expression in all species. We are investigating this regulation in human, viral, plant, microbial and fungal systems.
These projects involve the use of both computer (list of Brown group bioinformatic tools) and experimental tools to test for new types of translational control mechanisms. The recent availability of large amounts of sequence data, particularly complete genome sequences and transcriptomes and proteomes, has revolutionised the study of gene expression in many organisms.
For human studies, we take the approach of generating hypotheses regarding translational control from bioinformatics, then testing the ideas experimentally in tissue culture cells. We have developed new assays which utilise the power of modern microscopic, cell biological, and genomic techniques. The elements investigated include stability/instabilty elements e.g. Iron Responsive Elements ana AU rich elements and those for mRNA localisation in mammalian and yeast cells.
In human viral pathogens, for example HBV, we are focussing on discovering critical regulatory elements that may provide antiviral targets.
It is now possible to generate genome scale transcriptome and proteomic datasets for human cells. A striking finding from analysis of these studies is that the level of an mRNA typically predicts no more than 40% of the abundance of protein. This correlation represents the overall figure for all genes. We have developed a bioinformatic approach that distinguishes broad classes of genes using calculated translation efficiency (Translation Efficiency).
We are currently generating and analysing genome scale expression data from diverse species (RNA-Seq, microarrays) and proteomic data (pSILAC). These systems biology studies utilise whole transcriptome reference guided and de novo assembly and bioinformatic analysis of quantitative expression. They are aimed at finding not only changes in protein coding genes but also in regulatory RNAs and elements in mRNAs.
Our first tool (TransTerm) began over 20 years ago, it contains data related to translation. More recently a complementary database of known translational control elements has been established and included (TransTerm). We have recently extended this to include a curated database of structured Cis-regulatory RNA elements (CisRegRNA, 2012), and putative novel elements using CisRNA-SVM. Virus research tools and databases include HBVRegDB, VirusRegDB, MLOGD, CRISPRTarget.
Software, web servers, and datasets from the Brown group are available though our servers, by download, or through collaborators.
Genome annotation using comparative genomics
We are using high throughput RNA-Seq analysis to identify and characterise both mRNAs and ncRNAs from several diverse organisms, in collaboration with other groups (see collaborations). These studies include aiming to identify coding and non-coding RNAs and regulatory elements in these genomes. Applications include - plant pathogen and endophyte interactions, methanogen genomes, and pathogenic viral genomes and viromes.
Potential PhD (Doctoral) or MSc projects
There are several exciting projects available to students including Bioinformatics, Virology or Cell Biology or a mix of these. The balance of the approach would depend on the skills and interests of the person (e.g. Bioinformatics, Genetics, Genomics). These could be supervised in a collaboration (e.g. with CRIs or other Otago Researchers). Please send a CV including academic references and reason why you are interested in that project to me.
Indicative projects (for 2017-2018)
Discovery of viruses in metagenomic and virome sequences
Discovery of regulatory elements affecting human gene expression
Genomic and transcriptomic approaches to reducing agricultural greenhouse gas emissions (jointly supervised with collaborators).
Discovery of key features of the bacterial adaptive immune system (CRISPR-Cas). Jointly supervised by Dr Peter Fineran (Microbiology and Immunology).
Plant/Fungal interactions and genomics (with David Orlovich, Botany)
More information on fellowships and scholarships can be found on the University of Otago Postgraduate pages.
Artemio Mendoza (Bio-Protection, Lincoln) Genomics of fungal-plant interactions - Gene expression bioinformatics. Fungal non-coding RNAs.
Roger Hellens (QUT) and Richard MacKnight (Otago). Regulation of gene expression - mRNA analysis.
Torsten Kleffmann (Otago, Centre for Protein Research). The relationship between mRNA and protein levels in cells. High-throughput proteomic and RNA-Seq approaches.
Peter Fineran (Otago, Microbiology). The discovery of CRISPR elements in bacterial genomes and their targets in viral (bacteriophage) genomes.
Shannon Clark (AgResearch) and Prof Neil Gemmell (Anatomy). Greenshell Mussel genomics, Perna canalicula (Taonga).
David Orlovich and Tina Summerfield (Botany) New Zealand native mushroom genomes (Taonga).
Dan Garama (Monash) New Zealand Kina genomics, Evechinus chloroticus (Taonga)
Abigail Smith (Marine Science) Bryzoan genomics
Herve Le Hir (Paris) Gene Expression
Peter Revill (Melbourne) HBV expression
Genetics and Biochemistry: BIOC221, GENE223, BIOC352, BIOC451, GENE400, PLBI401, MICN201 (Genetics, Blood) MICN301 (Genetics).
I am interested in contacts from potential collaborators, post-doctoral fellows, and graduate students.
Chun Shen Lim and Chris M Brown., Hepatitis B virus nuclear export elements: RNA stem-loop α and β, key parts of the HBV post-transcriptional regulatory element., RNA Biol 2016 pp. 0-00., Link »
Monika Schmoll, Christoph Dattenböck, Nohemí Carreras-Villaseñor, Artemio Mendoza-Mendoza, Doris Tisch, Mario Ivan Alemán, Scott E Baker, Christopher Brown, Mayte Guadalupe Cervantes-Badillo, José Cetz-Chel, Gema Rosa Cristobal-Mondragon, Luis Delaye, Edgardo Ulises Esquivel-Naranjo, Alexa Frischmann, Jose de Jesus Gallardo-Negrete, Monica García-Esquivel, Elida Yazmin Gomez-Rodriguez, David R Greenwood, Miguel Hernández-Oñate, Joanna S Kruszewska, Robert Lawry, Hector M Mora-Montes, Tania Muñoz-Centeno, Maria Fernanda Nieto-Jacobo, Guillermo Nogueira Lopez, Vianey Olmedo-Monfil, Macario Osorio-Concepcion, Sebastian Piłsyk, Kyle R Pomraning, Aroa Rodriguez-Iglesias, Maria Teresa Rosales-Saavedra, J Alejandro Sánchez-Arreguín, Verena Seidl-Seiboth, Alison Stewart, Edith Elena Uresti-Rivera, Chih-Li Wang, Ting-Fang Wang, Susanne Zeilinger, Sergio Casas-Flores, and Alfredo Herrera-Estrella., The Genomes of Three Uneven Siblings: Footprints of the Lifestyles of Three Trichoderma Species., Microbiol Mol Biol Rev 2016 vol. 80 (1) pp. 205-327., Link »
Roger P Hellens, Chris M Brown, Matthew A W Chisnall, Peter M Waterhouse, and Richard C Macknight, The Emerging World of Small ORFs, Trends Plant Sci 2015, Link »
Donna M Bond, Nick W Albert, Robyn H Lee, Gareth B Gillard, Chris M Brown, Roger P Hellens, and Richard C Macknight., Infiltration-RNAseq: transcriptome profiling of Agrobacterium-mediated infiltration of transcription factors to discover gene function and expression networks in plants., Plant Methods 2016 vol. 12 (1) p. 41, Link »
Raymond H.J. Staals, Simon A. Jackson, Ambarish Biswas, Stan J.J. Brouns Chris M. Brown & Peter C. Fineran (2016) Interference-driven spacer acquisition is dominant over naive and primed adaptation in a native CRISPR–Cas system Nature Communications 12:12853 article link
Biswas, A., Staals, R. H., Morales, S. E., Fineran, P. C. & Brown, C. M. CRISPRDetect: a flexible algorithm to define CRISPR arrays. BMC Genomics 17, 356 (2016). article link
Biswas, A., Fineran, P. C., & Brown, C. M. (2015). Computational Detection of CRISPR/crRNA Targets. in Methods in Molecular Biology, 1311:77-89. article link
Davies, C, Chris Brown, Dana Westphal, Joanna Ward and Vernon K Ward (2015) Murine Norovirus replication induces a G0/G1 cell cycle arrest in asynchronous growing cells. J Virology 89:6057-6066 article link
Biswas, A., and CM Brown (2014) Scan for Motifs: A webserver for the analysis of post-transcriptional regulatory elements in the 3' untranslated regions (3' UTRs) of mRNAs. BMC Bioinformatics 15:174. article link Web application
Chen, A., N. Panjaworayan T-Thienprasert and CM Brown (2014) Prospects for inhibiting the post-transcriptional regulation of gene expression in hepatitis B virus. World Journal of Gastroenterology 20:7993-8004 article link
Biswas, A., P.C. Fineran and CM Brown (2014) Accurate computational prediction of the transcribed strand of CRISPR noncoding RNAs. Bioinformatics 30:1805-1813 article link
Waugh, E. Chen, A. Baird, M. Fleming, S. Brown, C.M. and V K. Ward (2014) Characterization of the chemokine response of RAW264.7 cells to infection by murine norovirus. Virus Genes 181:27-34.
SG Stevens and CM Brown (2014) Bioinformatic methods to discover cis-regulatory elements in mRNAs.
Chapter 10 in the "Springer Handbook of Bio-/Neuro-informatics" -pg: 151-169. Springer. Heidelberg. article link
Biswas A, Gagnon GG, Brouns SJJ, Fineran PC, CM Brown (2013) CRISPRTarget: Bioinformatic prediction and analysis of crRNA targets. RNA Biology 10:5 817-827 (CRISPRTarget)
XS Chen, CM Brown (2012) Computational identification of new structured cis-regulatory elements in the 3-UTR of human protein coding mRNAs. Nucleic Acids Research 40:8862-8873 (CisRNA-SVM web resources)
SJ Lange, D Maticzka, M Mohl, JN Gagnon, CM Brown and R Backofen (2012) Global or local? Predicting secondary structure and accessibility in mRNAs. Nucleic Acids Research 40:5215-5226 Feb 2012 (CisRegRNA)
Pilbrow AP, Folkersen L, Pearson JF, Brown CM, McNoe L, Wang NM, Sweet WE, Tang WH, Black MA, Troughton RW, Richards AM, Franco-Cereceda A, Gabrielsen A, Eriksson P, Moravec CS, Cameron VA (2012) The chromosome 9p21.3 coronary heart disease risk allele is associated with altered gene expression in normal heart and vascular tissues. PLoS One 7(6):e39574
Chen, A, and Brown, CM (2012) Distinct families of cis-acting RNA replication elements epsilon from hepatitis B viruses. RNA Biology 9:130-136 (first published online 25/12/2011) (web resources)
Panjaworayan N and C M. Brown (2011) Effects of HBV Genetic Variability on RNAi Strategies. Hepatitis Research and Treatment 4:2011.
Stevens, S.G., Gardner, P.P., and Brown, C. (2011) Two covariance models for iron-responsive elements. RNA Biology 8: 792-801. (web resources)
Panjaworayan, N, S Payungporn, Y Poovorawan, CM Brown (2010) Identification of an effective siRNA target site and functional regulatory elements, within the hepatitis B virus post-transcriptional regulatory element. Virology J 7:216
Milev, M, CM Brown and AJ Mouland (2010) Live cell visualization of the interactions between HIV-1 Gag and the cellular RNA-binding protein Staufen1 Retrovirology 7:41.
Jacobs, G.H., A. Chen, S.G. Stevens, P.A. Stockwell, M.A. Black, W.P. Tate, and CM Brown (2009) Transterm: a database to aid the analysis of regulatory sequences in mRNAs. Nucleic Acids Res, 37:D72-76. (web resources)
Panjaworayan, N, SK Roessner, AE Firth and CM Brown (2007) HBVRegDB: Annotation, comparison, detection and visualization of regulatory elements in hepatitis B virus sequences, Virology J 4:136 (web resources)
Zadissa, A, JC McEwan and CM Brown (2007) Inference of transcriptional regulation using gene expression data from the bovine and human genomes, BMC Genomics 8:265
Firth, A and Brown CM. (2006) Detecting overlapping coding sequences in virus genomes BMC Bioinformatics 7:173
GH Jacobs, PA Stockwell, WP Tate and Brown, CM (2006) Transtermextended search facilities and improved integration with other databases Nucleic Acids Res. 34:D37-D40
Chung B.Y.W., C. Simons, A. E. Firth, C.M. Brown and R. P. Hellens (2006) Effect of 5'UTR introns on gene expression in Arabidopsis thaliana. BMC Genomics 7:120
Chen, A., Y.F. Kao, and C.M. Brown (2005) Translation of the first upstream ORF in the hepatitis B virus pregenomic RNA modulates translation at the core and polymerase initiation codons. Nucleic Acids Res, 2005. 33:1169-1181.
Firth, A and Brown, CM (2005) Detecting overlapping coding sequences with pairwise alignments. Bioinformatics 21:282-292
Chapman, B and Brown, CM (2004) Translation termination in A. thaliana: characterisation of three versions of release factor 1. Gene 341:219-225
Rackham, O and Brown, CM (2004) Visualization of RNA-protein interactions in living cells: FMRP and IMP1 interact on mRNAs EMBO J 23:3346-3355