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Mikhail Gelfand Research and Training Center “Bioinformatics”

Comparative genomic analysis of T-box regulation: identification of new structural classes and reconstruction of evolution. Mikhail Gelfand Research and Training Center “Bioinformatics” Institute for Information Transmission Problems Moscow, Russia. Burnham Institute, October 2008

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Mikhail Gelfand Research and Training Center “Bioinformatics”

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  1. Comparative genomic analysis of T-box regulation: identification of new structural classes and reconstruction of evolution Mikhail Gelfand Research and Training Center “Bioinformatics” Institute for Information Transmission Problems Moscow, Russia Burnham Institute, October 2008 To Andrei Osterman on the occasioin of his Nth birthday

  2. T-boxes: the mechanism (Grundy & Henkin; Putzer & Grunberg-Manago)

  3. Partial alignment of predicted T-boxes TGG: T-box Aminoacyl-tRNA synthetases Amino acid biosynthetic genes Amino acid transporters

  4. … continued (in the 5’ direction) anti-anti (specifier) codon Aminoacyl-tRNA synthetases Amino acid biosynthetic genes Amino acid transporters

  5. Why T-boxes? • May be easily identified • In most cases functional specificity may be reliably predicted by the analysis of the specifier codons (anti-anti-codons) • Sufficiently long to retain phylogenetic signal => T-boxes are a good model of regulatory evolution

  6. 805 T-boxes in 96 bacteria • Firmicutes • aa-tRNA synthetases • enzymes • transporters • all amino acids excluding glutamate • Actinobacteria (regulation of translation – predicted) • branched chain (ileS) • aromatic (Atopobium minutum) • Delta-proteobacteria • branched chain (leu – enzymes) • Thermus/Deinococcus group (aa-tRNA synthases) • branched chain (ileS, valS) • glycine • Chloroflexi, Dictyoglomi • aromatic (trp – enzymes) • branched chain (ileS) • threonine

  7. Double and partially double T-boxes • TRP: trp operon (Bacillales, C. beijerincki, D. hafniense) • TYR: pah (B. cereus) • THR: thrZ (Bacillales); hom (C. difficile) • ILE: ilv operon (B. cereus) • LEU: leuA (C. thermocellum) • ILE-LEU: ilvDBNCB-leuACDBA (Desulfotomaculum reducens) • TRP: trp operon (T. tengcongensis) • PHE: arpLA-pheA (D. reducens, S. wolfei) • PHE: trpXY2 (D. reducens) • PHE: yngI (D. reducens) • TYR: yheL (B. cereus) • SER: serCA (D. hafniense) • THR: thrZ(S. uberis) • THR: brnQ-braB1 (C. thermocellum) • HIS: hisXYZ (Lactobacillales) • ARG: yqiXYZ (C. difficile)

  8. Predicted regulation of translation:ileS in many Actinobacteria • Instead of the terminator, the sequester hairpin (hides the translation initiation site) • Same mechanism regulates different processes – cf. riboswitches

  9. A new type of translational T-boxes in Actinobacteria • Shorter specifier hairpin • Anti-anti-codon in the “head” loop, not a bulge loop • A majority of cases (all except Streptomyces spp.)

  10. Same enzymes – different regulators (common part of the aromatic amino acids biosynthesis pathway) cf. E.coli: aroF,G,H: feedback inhibition by TRP, TYR, PHE; transcriptional regulation by TrpR, TyrR

  11. Recent duplications and bursts: ARG-T-box in Clostridium difficile

  12. … caused by loss of transcription factor AhrC

  13. Duplications and changes in specificity: ASN/ASP/HIS T-boxes

  14. Blow-up 1

  15. Blow-up 2. Prediction Regulators lost in lineages with expanded HIS-T-box regulon??

  16. … and validation • conserved motifs upstream of HIS biosynthesis genes • candidate transcription factor yerC co-localized with the his genes • present only in genomes with the motifs upstream of the his genes • genomes with neither YerC motif nor HIS-T-boxes: attenuators Bacillales(his operon) Clostridiales Thermoanaerobacteriales Halanaerobiales Bacillales

  17. New histidine transporters • hisXYZ(The ATP-binding Cassette (ABC) Superfamily)Firmicutes • yuiF(Na+/H+ antiporter, NahC family)Bacillales, some Clostridiales(regulated by his-attenuator in Haemophilus inlfuenzae) • Cphy_3090(SSS sodium solute transporter superfamily)Clostridiales, Thermoanaerobacteriales, Halanaerobiales

  18. The evolutionary history of the his genes regulation in the Firmicutes

  19. More duplications: THR-T-box in C. difficileand B. cereus

  20. Duplications and changes in specificity: branched-chain amino acids ATC CTC ATC

  21. Blow-up transporter: ATC GTC dual regulation of common enzymes: ATC CTC

  22. Three regulatory systems for the methionine bio-synthesis • SAM-dependent riboswitch • Met-T-box C. MtaR: repressor of transcription MtaR

  23. Methionine regulatory systems: loss of S-box regulons ZOO • S-boxes (SAM-1 riboswitch) • Bacillales • Clostridiales • the Zoo: • Petrotoga • actinobacteria (Streptomyces, Thermobifida) • Chlorobium, Chloroflexus, Cytophaga • Fusobacterium • Deinococcus • proteobacteria (Xanthomonas, Geobacter) • Met-T-boxes (Met-tRNA-dependent attenuator) + SAM-2 riboswitch for metK • Lactobacillales • candidate TF-binding motif: MtaR • Streptococcales Lact. Strep. Bac. Clostr.

  24. Summary / History

  25. Acknowledgements • Alexei Vitreschak • Andrei Mironov (software) • Galina Kovaleva (methionine) • Dmitry Rodionov, Burnham (early work on methionine and S-boxes) • HHMI • RFBR • RAS (program “Molecular and Cellular Biology”)

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