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
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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 - PowerPoint PPT Presentation
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Comparative genomic analysis of T-box regulation:
identification of new structural classes and reconstruction of
evolution
Mikhail GelfandResearch and Training Center “Bioinformatics”
Institute for Information Transmission ProblemsMoscow, Russia
Burnham Institute, October 2008To Andrei Osterman
on the occasioin of his Nth birthday
T-boxes: the mechanism (Grundy & Henkin; Putzer & Grunberg-
• 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)
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
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.)
Same enzymes – different regulators (common part of the aromatic amino acids biosynthesis pathway)
P H E T Y R
trpE
P E P E 4 P
D A H P
S H IK IM AT E
C H O R IS M AT E
trpDCFBA
tyrA hisC aspB
phhA
aroF
aroI aroE
aroA
aroD
aroB
aroC
aroA pheB aroH
yhaG
T R P
T R P
k in u ren in e p a th w ay
A N T H R A N IL AT E
F O L AT E
pabA pabB
A D C
trpG
TRP trpXYZ
TRP\PHE yocR fam ily
TYR yheL
aro:Regulated by TYR (BC)Regulated by PHE (SW O, DRE, HMO, CH, MTH, CTH)Regulated by TRP (DE, DEH)
cf. E.coli: aroF,G,H: feedback inhibition by TRP, TYR, PHE; transcriptional regulation by TrpR, TyrR
Recent duplications and bursts: ARG-T-box in Clostridium difficile
LJ_ARGS
LME_ARGS
LR_ARGS
LP_ARGS
CBE_ARGS
CPE_ARGSCB_ARGS
CTC_ARGS
CAC_ARGS
CDF_YQIXYZ
RDF02391
СDF_ARGC
CDF_ARGH
BC_ARGS2EF_ARGS
BH_ARGS
LSA_ARGSPPE_ARGS
LGA_ARGS
Bacillales
argSyqiXYZ
RDF02391
argCJBDF
predictedamino acidtransporters
NEW
argG
argH
Clostridiumdifficile
amino acidbiosynthetic genes
: ARG-specific T-box regulatory site
aminoacyl-tRNA synthetase
biosynthetic genes
amino acid transporters
NEW
Lactobacillales Clostridiales
argS argS
others
… caused by loss of transcription factor AhrC
Expansion of T-box regulon
regulation of expression of arginine biosynthetic and transport genes by T-box antitermination
: ARG-specific T-box regulatory site
Binding to 5’ UTR gene region regulation of gene expression
Other clostridia spp. (CA, CTC, CTH, CPE, CB, CPE)
yqiXYZ
argC
argH
yqiXYZ
argC
argG
argH
AhrC regulatory protein (negative regulation of arginine metabolism positive regulation of arginine catabolism)
...AhrC site
: AhrC binding site
Gram+ bacteria: Clostridiumdifficile:
AhrC is lost
5’
Duplications and changes in specificity: ASN/ASP/HIS T-boxes
CB_ASNS2
CDF_ASNA
EF_HISS
EX_HISS
BCL_HISSBH_HISS
OB_HISS
BC_HISS
TTE_HISS
DRE_HISS
CH_HISSCTH_HISS
PL_HISS
BE_HISSBL_HISS
BS_HISS
LME_HISXYZCDF_HISZX
LRE_HISXYZLSA_HISXYZ
OOE_HISXYZ
LP_HISXYZ
SGO_HISC
SMU_HISC
EF_HISXYZ
LMO_HISXYZ
EF_HISXYZ
LME_HIS(Z G\ )
LL_HISCLP_HISZ
LCA_HISZCB_ASNS3
CAC_ASNS32
BC_ASNS2
PPE_HISXYZ
PPE_ASNS
LB_ASNA
LD_ASNALJ_ QHMPgln
LJ_ASNA
PPE_ASNALP_ASNA
EX_ASNA
LB_ASNS2
CTC_ASNS2
PPE_HISSLP_HISS
LB_HISS
LJ_HISS
LRE_HISS
LRE_ASPS
LCA_HISS
CPE_ASNA
BC_ASNACBE_ASNS2
CTC_ASNACDF_ASNS2
CPE_ASNS2
his operon
his XYZ
Lactobacilla les
NEW
hisS
Other Gram +
ASP\ASN
HIS
Bacillales
HIS
aspS
SMU_ASPS2SG_ASPS2glnQHMP
L. johnsoniiasnA
ASP
ASN
asnAASN
Lac acillalestobasnS
ASN
aspS
hisXYZ
P. pentosaceus
asnS
HIS
ASP
Clostridiales
asnAASN
ASN
asnA
asnS
asnA
ASP
Rapid m utation of regulatory codons
ASN
AACGAC
hisSASP
Lac acillalestob
HIS
ASPhisS
L. reuteriaspS
ASN
ASN
ASN
ASN
Blow-up 1
PPE_ASNS2
LB_ASNA
LD_ASNALJ_GLNQHMP
LJ_ASNA
PPE_ASNALP_ASNA
PPE_HISSLP_HISS
LB_HISS
LJ_HISS
LRE_HISS
LRE_ASPS
LCA_HISS
aspShisSASP
Lac acillalestob
HIS ASPhisS
L. reuteri
aspS
ASP HIS
CACGAC
asnAASN
Lac acillalestob
disruption of hisS-aspS operonmutation of regulatory codon
L. johnsonii
asnA
ASP
ASN
glnQHMP
PPE_HISXYZ
ASN
AAC
P. pentosaceus
HIS
ASPhisXYZ
asnS
HIS
CAC
ASPASN
AAC GAC
Blow-up 2. Prediction
Regulators lost in lineages with expanded HIS-T-box regulon??
… 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
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)