Research

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Simon  Dove, PhD

Simon Dove, PhD
Department:
Medicine Research
Division
Infectious Diseases Research
Hospital Title:
Research Associate
Academic Title:
Associate Professor of Pediatrics, Harvard Medical School
Research Focus Area:
Transcription Regulation
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Research Overview

Successful infection of a host organism by a bacterial pathogen depends critically on its ability to make the appropriate virulence factors at the right time and place. This is achieved through the coordinate regulation of virulence genes, the expression of which is typically controlled at the level of transcription by proteins that modulate the activity of RNA polymerase (RNAP). Research in my laboratory focuses on the regulation of transcription in pathogenic bacteria with emphasis on regulators that contact RNAP, and regulators that control virulence gene expression.

Several current projects concern the regulation of virulence gene expression in Pseudomonas aeruginosa, a pathogen that infects the lungs of cystic fibrosis (CF) patients. In the chronically infected CF lung the organism persists as a biofilm—a surface attached community of bacteria encased in a polymeric matrix. Prominent amongst those genes that play a role in biofilm formation in P. aeruginosa are the cupA genes, which encode components of a putative fimbrial structure that facilitates surface-attachment. We have found that MvaT, a member of the H-NS family of proteins, controls the phase-variable (i.e. ON/OFF) expression of the cupA fimbrial gene cluster. Current work is aimed at determining how MvaT exerts this control.

Other work in the laboratory involves the study of two related transcription regulators from the intracellular pathogen Francisella tularensis, the causative agent of tularemia. These two regulators form a complex that associates with RNAP to positively control virulence gene expression in this organism. We are interested in determining how these regulators, which do not appear to bind DNA, influence the expression of specific target genes.

We have begun to investigate the role that small 2-4 nucleotide RNA transcripts, “nanoRNAs” play in the regulation of gene expression in bacteria. We have shown that nanoRNAs can prime transcription initiation in vivo and that when they do this results in large and widespread changes in gene expression. These findings establish that small RNA primers can be used to initiate transcription in vivo, challenging the conventional view that all cellular transcription occurs using only NTPs. Our findings further suggest that nanoRNAs could represent a distinct class of functional small RNAs that can affect gene expression through direct incorporation into a target RNA transcript rather than through a traditional antisense-based mechanism.

About Simon Dove

Simon Dove received his PhD from the University of Dundee in the UK and undertook Postdoctoral training in the Department of Microbiology and Molecular Genetics at Harvard Medical School.

Key Publications

  •  Goldman, S.R., Sharp, J.S., Vvedenskaya, I.O., Livny, J., Dove, S.L., and Nickels, B.E. (2011) NanoRNAs prime transcription initiation in vivo. Mol. Cell 42, 817-825.
  • Castang, S., and Dove, S.L. (2010) High-order oligomerization is required for the function of the H-NS family member MvaT in Pseudomonas aeruginosaMol. Microbiol. 78, 916-931.
  • Charity, J.C., Blalock, L.T., Costante-Hamm, M.M., Kasper, D.L., and Dove, S.L. (2009) Small molecule control of virulence gene expression in Francisella tularensis. PLoS Pathog. 5, e1000641.
  • Turner, K.H., Vallet-Gely, I., and Dove, S.L. (2009) Epigenetic control of virulence gene expression in Pseudomonas aeruginosa by a LysR-type transcription regulator. PLoS Genet. 5, e1000779.

Publications

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  1. Ramsey KM, Dove SL. A response regulator promotes Francisella tularensis intramacrophage growth by repressing an anti-virulence factor. Mol Microbiol. 2016 Aug; 101(4):688-700.
  2. Druzhinin SY, Tran NT, Skalenko KS, Goldman SR, Knoblauch JG, Dove SL, Nickels BE. A Conserved Pattern of Primer-Dependent Transcription Initiation in Escherichia coli and Vibrio cholerae Revealed by 5' RNA-seq. PLoS Genet. 2015 Jul; 11(7):e1005348.
  3. McFarland KA, Dolben EL, LeRoux M, Kambara TK, Ramsey KM, Kirkpatrick RL, Mougous JD, Hogan DA, Dove SL. A self-lysis pathway that enhances the virulence of a pathogenic bacterium. Proc Natl Acad Sci U S A. 2015 Jul 7; 112(27):8433-8.
  4. Ding P, McFarland KA, Jin S, Tong G, Duan B, Yang A, Hughes TR, Liu J, Dove SL, Navarre WW, Xia B. A Novel AT-Rich DNA Recognition Mechanism for Bacterial Xenogeneic Silencer MvaT. PLoS Pathog. 2015 Jun; 11(6):e1004967.
  5. Ramsey KM, Osborne ML, Vvedenskaya IO, Su C, Nickels BE, Dove SL. Ubiquitous promoter-localization of essential virulence regulators in Francisella tularensis. PLoS Pathog. 2015 Apr; 11(4):e1004793.
  6. Rohlfing AE, Dove SL. Coordinate control of virulence gene expression in Francisella tularensis involves direct interaction between key regulators. J Bacteriol. 2014 Oct; 196(19):3516-26.
  7. Balasubramanian D, Kumari H, Jaric M, Fernandez M, Turner KH, Dove SL, Narasimhan G, Lory S, Mathee K. Deep sequencing analyses expands the Pseudomonas aeruginosa AmpR regulon to include small RNA-mediated regulation of iron acquisition, heat shock and oxidative stress response. Nucleic Acids Res. 2014 Jan; 42(2):979-98.
  8. Jackson AA, Gross MJ, Daniels EF, Hampton TH, Hammond JH, Vallet-Gely I, Dove SL, Stanton BA, Hogan DA. Anr and its activation by PlcH activity in Pseudomonas aeruginosa host colonization and virulence. J Bacteriol. 2013 Jul; 195(13):3093-104.
  9. Castang S, Dove SL. Basis for the essentiality of H-NS family members in Pseudomonas aeruginosa. J Bacteriol. 2012 Sep; 194(18):5101-9.
  10. Winardhi RS, Fu W, Castang S, Li Y, Dove SL, Yan J. Higher order oligomerization is required for H-NS family member MvaT to form gene-silencing nucleoprotein filament. Nucleic Acids Res. 2012 Oct; 40(18):8942-52.
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  12. Vvedenskaya IO, Sharp JS, Goldman SR, Kanabar PN, Livny J, Dove SL, Nickels BE. Growth phase-dependent control of transcription start site selection and gene expression by nanoRNAs. Genes Dev. 2012 Jul 1; 26(13):1498-507.
  13. Li M, Le Trong I, Carl MA, Larson ET, Chou S, De Leon JA, Dove SL, Stenkamp RE, Mougous JD. Structural basis for type VI secretion effector recognition by a cognate immunity protein. PLoS Pathog. 2012; 8(4):e1002613.
  14. Basset A, Turner KH, Boush E, Sayeed S, Dove SL, Malley R. An epigenetic switch mediates bistable expression of the type 1 pilus genes in Streptococcus pneumoniae. J Bacteriol. 2012 Mar; 194(5):1088-91.
  15. McManus HR, Dove SL. The CgrA and CgrC proteins form a complex that positively regulates cupA fimbrial gene expression in Pseudomonas aeruginosa. J Bacteriol. 2011 Nov; 193(22):6152-61.
  16. Basset A, Turner KH, Boush E, Sayeed S, Dove SL, Malley R. Expression of the type 1 pneumococcal pilus is bistable and negatively regulated by the structural component RrgA. Infect Immun. 2011 Aug; 79(8):2974-83.
  17. Cho H, McManus HR, Dove SL, Bernhardt TG. Nucleoid occlusion factor SlmA is a DNA-activated FtsZ polymerization antagonist. Proc Natl Acad Sci U S A. 2011 Mar 1; 108(9):3773-8.
  18. Karna SL, Zogaj X, Barker JR, Seshu J, Dove SL, Klose KE. A bacterial two-hybrid system that utilizes Gateway cloning for rapid screening of protein-protein interactions. Biotechniques. 2010 Nov; 49(5):831-3.
  19. Castang S, Dove SL. High-order oligomerization is required for the function of the H-NS family member MvaT in Pseudomonas aeruginosa. Mol Microbiol. 2010 Nov; 78(4):916-31.
  20. Charity JC, Blalock LT, Costante-Hamm MM, Kasper DL, Dove SL. Small molecule control of virulence gene expression in Francisella tularensis. PLoS Pathog. 2009 Oct; 5(10):e1000641.
  21. Castang S, McManus HR, Turner KH, Dove SL. H-NS family members function coordinately in an opportunistic pathogen. Proc Natl Acad Sci U S A. 2008 Dec 2; 105(48):18947-52.
  22. Vallet-Gely I, Sharp JS, Dove SL. Local and global regulators linking anaerobiosis to cupA fimbrial gene expression in Pseudomonas aeruginosa. J Bacteriol. 2007 Dec; 189(23):8667-76.
  23. Charity JC, Costante-Hamm MM, Balon EL, Boyd DH, Rubin EJ, Dove SL. Twin RNA polymerase-associated proteins control virulence gene expression in Francisella tularensis. PLoS Pathog. 2007 Jun; 3(6):e84.
  24. Vallet-Gely I, Donovan KE, Fang R, Joung JK, Dove SL. Repression of phase-variable cup gene expression by H-NS-like proteins in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2005 Aug 2; 102(31):11082-7.
  25. Rietsch A, Vallet-Gely I, Dove SL, Mekalanos JJ. ExsE, a secreted regulator of type III secretion genes in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2005 May 31; 102(22):8006-11.
  26. Sun L, Dove SL, Panaghie G, deHaseth PL, Hochschild A. An RNA polymerase mutant deficient in DNA melting facilitates study of activation mechanism: application to an artificial activator of transcription. J Mol Biol. 2004 Nov 5; 343(5):1171-82.
  27. Harnasch M, Grau S, Behrends C, Dove SL, Hochschild A, Iskandar MK, Xia W, Ehrmann M. Characterization of presenilin-amyloid precursor interaction using bacterial expression and two-hybrid systems for human membrane proteins. Mol Membr Biol. 2004 Nov-Dec; 21(6):373-83.
  28. Dove SL, Hochschild A. A bacterial two-hybrid system based on transcription activation. Methods Mol Biol. 2004; 261:231-46.
  29. Song T, Dove SL, Lee KH, Husson RN. RshA, an anti-sigma factor that regulates the activity of the mycobacterial stress response sigma factor SigH. Mol Microbiol. 2003 Nov; 50(3):949-59.
  30. Dove SL, Darst SA, Hochschild A. Region 4 of sigma as a target for transcription regulation. Mol Microbiol. 2003 May; 48(4):863-74.
  31. Dove SL. Studying protein-protein interactions using a bacterial two-hybrid system. Methods Mol Biol. 2003; 205:251-65.
  32. Nickels BE, Dove SL, Murakami KS, Darst SA, Hochschild A. Protein-protein and protein-DNA interactions of sigma70 region 4 involved in transcription activation by lambdacI. J Mol Biol. 2002 Nov 15; 324(1):17-34.
  33. Shaywitz AJ, Dove SL, Greenberg ME, Hochschild A. Analysis of phosphorylation-dependent protein-protein interactions using a bacterial two-hybrid system. Sci STKE. 2002 Jul 23; 2002(142):pl11.
  34. Pande S, Makela A, Dove SL, Nickels BE, Hochschild A, Hinton DM. The bacteriophage T4 transcription activator MotA interacts with the far-C-terminal region of the sigma70 subunit of Escherichia coli RNA polymerase. J Bacteriol. 2002 Jul; 184(14):3957-64.
  35. Kuznedelov K, Minakhin L, Niedziela-Majka A, Dove SL, Rogulja D, Nickels BE, Hochschild A, Heyduk T, Severinov K. A role for interaction of the RNA polymerase flap domain with the sigma subunit in promoter recognition. Science. 2002 Feb 1; 295(5556):855-7.
  36. Kelley MT, Bürckstümmer T, Wenzel-Seifert K, Dove S, Buschauer A, Seifert R. Distinct interaction of human and guinea pig histamine H2-receptor with guanidine-type agonists. Mol Pharmacol. 2001 Dec; 60(6):1210-25.
  37. Dove SL, Hochschild A. Bacterial two-hybrid analysis of interactions between region 4 of the sigma(70) subunit of RNA polymerase and the transcriptional regulators Rsd from Escherichia coli and AlgQ from Pseudomonas aeruginosa. J Bacteriol. 2001 Nov; 183(21):6413-21.
  38. Dove SL, Huang FW, Hochschild A. Mechanism for a transcriptional activator that works at the isomerization step. Proc Natl Acad Sci U S A. 2000 Nov 21; 97(24):13215-20.
  39. Danese PN, Pratt LA, Dove SL, Kolter R. The outer membrane protein, antigen 43, mediates cell-to-cell interactions within Escherichia coli biofilms. Mol Microbiol. 2000 Jul; 37(2):424-32.
  40. Blum JH, Dove SL, Hochschild A, Mekalanos JJ. Isolation of peptide aptamers that inhibit intracellular processes. Proc Natl Acad Sci U S A. 2000 Feb 29; 97(5):2241-6.
  41. Hochschild A, Dove SL. Protein-protein contacts that activate and repress prokaryotic transcription. Cell. 1998 Mar 6; 92(5):597-600.
  42. Dove SL, Hochschild A. Conversion of the omega subunit of Escherichia coli RNA polymerase into a transcriptional activator or an activation target. Genes Dev. 1998 Mar 1; 12(5):745-54.
  43. Dove SL, Hochschild A. Use of artificial activators to define a role for protein-protein and protein-DNA contacts in transcriptional activation. Cold Spring Harb Symp Quant Biol. 1998; 63:173-80.
  44. Dove SL, Joung JK, Hochschild A. Activation of prokaryotic transcription through arbitrary protein-protein contacts. Nature. 1997 Apr 10; 386(6625):627-30.
  45. Dove SL, Smith SG, Dorman CJ. Control of Escherichia coli type 1 fimbrial gene expression in stationary phase: a negative role for RpoS. Mol Gen Genet. 1997 Mar 18; 254(1):13-20.
  46. Dove SL, Dorman CJ. Multicopy fimB gene expression in Escherichia coli: binding to inverted repeats in vivo, effect on fimA gene transcription and DNA inversion. Mol Microbiol. 1996 Sep; 21(6):1161-73.
  47. Dove SL, Dorman CJ. The site-specific recombination system regulating expression of the type 1 fimbrial subunit gene of Escherichia coli is sensitive to changes in DNA supercoiling. Mol Microbiol. 1994 Dec; 14(5):975-88.
  48. Shaywitz AJ, Dove SL, Kornhauser JM, Hochschild A, Greenberg ME. Magnitude of the CREB-dependent transcriptional response is determined by the strength of the interaction between the kinase-inducible domain of CREB and the KIX domain of CREB-binding protein. Mol Cell Biol. 2000 Dec; 20(24):9409-22.
  49. Turner KH, Vallet-Gely I, Dove SL. Epigenetic control of virulence gene expression in Pseudomonas aeruginosa by a LysR-type transcription regulator. PLoS Genet. 2009 Dec; 5(12):e1000779.
  50. Yuan AH, Gregory BD, Sharp JS, McCleary KD, Dove SL, Hochschild A. Rsd family proteins make simultaneous interactions with regions 2 and 4 of the primary sigma factor. Mol Microbiol. 2008 Dec; 70(5):1136-51.
  51. Nickels BE, Dove SL. NanoRNAs: a class of small RNAs that can prime transcription initiation in bacteria. J Mol Biol. 2011 Oct 7; 412(5):772-81.
  52. Johnson SJ, Close D, Robinson H, Vallet-Gely I, Dove SL, Hill CP. Crystal structure and RNA binding of the Tex protein from Pseudomonas aeruginosa. J Mol Biol. 2008 Apr 11; 377(5):1460-73.
  53. Brencic A, McFarland KA, McManus HR, Castang S, Mogno I, Dove SL, Lory S. The GacS/GacA signal transduction system of Pseudomonas aeruginosa acts exclusively through its control over the transcription of the RsmY and RsmZ regulatory small RNAs. Mol Microbiol. 2009 Aug; 73(3):434-45.
  54. Goldman SR, Sharp JS, Vvedenskaya IO, Livny J, Dove SL, Nickels BE. NanoRNAs prime transcription initiation in vivo. Mol Cell. 2011 Jun 24; 42(6):817-25.
  55. Winardhi RS, Castang S, Dove SL, Yan J. Single-molecule study on histone-like nucleoid-structuring protein (H-NS) paralogue in Pseudomonas aeruginosa: MvaU bears DNA organization mode similarities to MvaT. PLoS One. 2014; 9(11):e112246.
  56. McGuffie BA, Vallet-Gely I, Dove SL. s Factor and Anti-s Factor That Control Swarming Motility and Biofilm Formation in Pseudomonas aeruginosa. J Bacteriol. 2015 Nov 30; 198(5):755-65.
  57. Eshraghi A, Kim J, Walls AC, Ledvina HE, Miller CN, Ramsey KM, Whitney JC, Radey MC, Peterson SB, Ruhland BR, Tran BQ, Goo YA, Goodlett DR, Dove SL, Celli J, Veesler D, Mougous JD. Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth. Cell Host Microbe. 2016 Nov 9; 20(5):573-583.
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