Thyroid hormone receptor orthologues from invertebrate species with emphasis on Schistosoma mansoni
© Wu et al; licensee BioMed Central Ltd. 2007
Received: 03 April 2007
Accepted: 29 August 2007
Published: 29 August 2007
Thyroid hormone receptors (TRs) function as molecular switches in response to thyroid hormone to regulate gene transcription. TRs were previously believed to be present only in chordates.
We isolated two TR genes from the Schistosoma mansoni and identified TR orthologues from other invertebrates: the platyhelminths, S. japonium and Schmidtea mediterranea, the mollusc, Lottia gigantean and the arthropod Daphnia pulex. Phylogenetic analysis of the DNA binding domain and/or ligand binding domain shows that invertebrate and vertebrate TRs cluster together, TRs from the vertebrates and from the jawless vertebrate (lamprey) clustered within separate subgroups, Platyhelminth TRs cluster outside of the vertebrate TR subgroups and that the schistosome TRs and S. mediterranea TRs clustered within separate subgroups.
Alignment of the C-terminus of the A/B domain revealed a conserved TR-specific motif, termed TR 'N-terminus signature sequence', with a consensus sequence of (G/P)YIPSY(M/L)XXXGPE(D/E)X.
Heterodimer formation between S. mansoni TRs and SmRXR1 suggests that the invertebrate TR protein gained the ability to form a heterodimer with RXR. ESMA analysis showed that SmTRα could bind to a conserved DNA core motif as a monomer or homodimer.
Vertebrate TR genes originated from a common ancestor of the Bilateria. TR genes underwent duplication independently in the Protostomia and Deuterostomia. The duplication of TRs in deuterostomes occurred after the split of jawless and jawed vertebrates. In protostomes, TR genes underwent duplication in Platyhelminths, occurring independently in trematode and turbellarian lineages. Using S. mansoni TRs as an example, invertebrate TRs exhibited the ability to form a dimer with RXR prior to the emergence of the vertebrate TRs and were able to bind to vertebrate TR core DNA elements as a monomer or homodimer.
Thyroid hormones (TH) play important roles in growth, development and metabolism in vertebrates. TH is synthesized in the thyroid gland under the control of thyroid-stimulating hormone (TSH) secreted by the pituitary. TSH secretion is controlled by thyrotropin-releasing hormone (TRH) which is secreted from the hypothalamus. THs are lipophilic molecules able to passively cross the membrane and bind to its receptor, the thyroid hormone receptor (TR). TRs belong to a superfamily of transcription factors called nuclear receptor (NR) superfamily, based on protein sequence similarities, structural motifs and functionality . TRs function as a molecular switch in response to the thyroid hormones T3 or T4 to activate or repress gene transcription depending on the promoter context and thyroid hormone binding status . The typical nuclear receptor contains an N-terminal A/B domain, a conserved C domain (DNA binding domain, DBD), a D domain (hinge region) and a moderately conserved E domain (ligand binding domain, LBD). The most conserved DBD contains two zinc finger motifs (CI and CII). Like all NRs, TRs regulate transcription through its binding to the promoter region of a target gene by the DBD and they activate or repress mRNA synthesis through co-regulators bound to the LBD . The specific target DNA sequence to which NRs bind is called a hormone response element (HRE). The typical HRE is a direct, inverted or everted repeat or palindrome of the DNA sequence AGGTCA. TRs can bind to the HRE as a monomer, a homodimer or as a heterodimer with RXR, another member of nuclear receptor superfamily which contributes to the specificity of the TR. TH binds to the LBD of TR which results in a conformational change in the C-terminus of the receptor. Corepressors then dissociated from the TR allowing coactivators to bind to the C-terminus of the TR in a hormone-dependent manner. TR and the coactivator complex activate the expression of the target gene [3, 4].
TR was previously believed to be an innovation of chordates as the genomes of insects (Drosophila and mosquito) and nematodes (Caenorhabditis elegans and C. briggus) do not contain TR genes [5–8]. Recently, we identified two thyroid receptor homologues in the flatworm Schistosoma mansoni , one of which was found in the S. mansoni EST database [6, 10]. The presence of TR homologues in S. mansoni demonstrated that the TR orthologue genes are present outside of chordates. However, it is still unclear whether these prostostome TRs possess the same functional domains as in vertebrate TRs. Another question is whether the TR orthologue is present in other invertebrates or just in the platyhelminth lineage? Answers to these questions will help to understand the origin of TR genes and evolution of the function of vertebrate thyroid hormone network. To begin to address these questions, we isolated cDNAs of S. mansoni TRs and demonstrated that TRs in platyhelminths are highly conserved not only in sequence similarity, but also in gene organization, protein-protein interaction and in DNA-binding ability. Furthermore, we mined the available genome data and demonstrated that TR orthologues are present in different invertebrate animals but not in Porifera or Cnidaria. Phylogenetic analysis showed that the TR orthologue likely originated from a common ancestor of the Bilateria.
TR orthologue genes in invertebrate animals
Sequence alignment analysis
Alignment of DBD amino acid sequences show that the invertebrate TR orthologues are highly conserved (Fig. 1). All TRs (from chordate and non-chordate species) possess an identical P-box sequence, which determines the specificity of target DNA binding. The methionine at position 16 of the N-terminus of the DBD (highlighted in red in Fig. 1) was non-chordate TR-specific. Instead at this position an isoleucine is conserved in all chordate TRs examined to date. Two amino acids (His and Pro) at positions 33–34 of N-terminal of DBD were chordate TR-specific (highlighted blue in Fig. 1). The second zinc finger is less conserved in non-chordate TR orthologues compared to the first zinc finger, but still shows a high degree of conservation (Fig. 1). The T-box and A-box which are located in the C-terminal extension (CTE) of the DBD are also highly conserved in non-chordate TR orthologues. They show 75–83% and 57–100% identity to the chordate T-box and A-box, respectively. These regions in the water flea TR orthologue are highly divergent, probably due to a recombination event that happened in this region (see below). An aspartic acid in the vertebrate TRs at the 8th position of N-terminus of the T-box is highly conserved for jawed vertebrate TRs, a glutamic acid at this position is conserved in other TRs. Although the N-terminal A/B domain of nuclear receptors is divergent, there is a highly conserved motif found at the 3' end of the TR A/B domain, we termed the 'N-terminal signature sequence' (NTSS). The TR NTSS is a consensus sequence of (G/P)YIPSY(M/L)XXXGPE(D/E) (Fig. 1). In non-chordate TR orthologues, the sequence is PYIPSYMXXXGPEEP; while in chordates, three amino acids are deleted generating a sequence of GYIPYL(D/E)KE(P/Q/L). The deleted three amino acids in chordate NTSS were deduced from the non-chordate sea urchin TR (SpTR). Since the deuterostome SpTR shares the same NTSS with that of protostome TRs, this suggests that the non-chordate NTSS is the primitive state.
Functional domains of non-chordate TRs
To determine the functional domains of a non-chordate TR orthologue, cDNAs encoding the entire open reading frame (ORF) of the two S. mansoni TRs (SmTRα and SmTRβ) were isolated, sequenced and the sequences deposited in GenBank (SmTRα [GenBank:AY395038, AY395059–AY395063, AH013464) and SmTRβ [GenBank:AY395039]).
The gene organization of the TR homologue genes in S. mansoni (SmTRα and SmTRβ) was identified by alignment of the cDNA sequence with the genomic sequence (Fig. 3). The genomic sequences were obtained by screening S. mansoni bacterial artificial chromosome (BAC) libraries (SmBAC1 or CHOR103) and sequencing the BAC DNA , and by Blast searching WTSI S. mansoni WGS database . Three clones (SmBAC1 3A6, 4G3 and 9D10) for SmTRα and 3 clones (CHOR103 3I15, 7K22 and 21F18) for SmTRβ were identified by screening the BAC libraries. A gDNA contig (Sm00.scaff00056.0030.1) for SmTRα and a gDNA contig (Sm00.scaff00631.0050) for SmTRβ were obtained from WTSI S. mansoni WGS database. The Contig Sm00.scaff00056.0030.1 contains a partial coding region for SmTRα, BAC DNAs (SmBAC1 3A6 and 4G3) were sequenced to generate a contig which contained full coverage of SmTRα cDNA sequence.
The ORF of SmTRα is encoded by seven exons spanning over 32 kb and the ORF of SmTRβ is encoded by six exons spanning over 21 kb (Fig. 3). All splice donor and acceptor sites for the two genes fit the GT-AG role. The A/B domain, hinge and E domains (LBD) are each encoded by 2–3 exons, respectively. The DBD of both proteins is encoded by one exon (Fig. 3). The 5' UTR and 3'UTR in both SmTRα and SmTRβ were not determined due to a short 3'UTR in SmTRα which seems not to be full length and due to the genomic contig not covering the 5'- and 3'UTR for SmTRβ.
An extensive search of whole genomic sequence (WGS) databases extracted from NCBI and online resources revealed the presence of TR orthologues in the Platyhelminths, Mollusca, Crustacea, and Echinodermata. However, no TR orthologues nor sequences encoding a TR P-box sequence of CEGCKG followed by the amino acid sequence FFRR (CEGCKGFFRR), which is unique to NR subfamily 1 including TR, was found in sponges (Reniera sp) nor cnidarians (Hydra magnipapillata and Nematostella vectensis). The results suggested that the TR orthologue gene originated in a common ancestor of the Bilateria. The gene duplication of TRs was deduced from a phylogenetic analysis employing DBD and LBD sequences. The analyses demonstrated that the TR orthologue genes underwent duplication independently in invertebrates and vertebrates. Furthermore, the TR orthologues in the Platyhelminths underwent duplication after the split of the turbellaria and trematodes. In vertebrates, the TR genes underwent a duplication event in lampreys, a jawless vertebrate, after the lamprey split from a common ancestor of jawed vertebrates. This result is consistent with the duplication of Hox gene clusters in lampreys . Although the A/B domain of NR is highly divergent, we identified a conserved NTSS (N-terminal signature sequence, (G/P)YIPSY(M/L)XXXGPE(D/E)) located in the C-terminus of the A/B domain of TRs. Analysis of other NRs (data not shown) demonstrates this motif is found only in TRs suggesting it is TR-specific. The NTSS of TRs was found to be sequence-specific for the chordate and for the non-chordate TRs, three amino acids present in non-chordate TRs are missing in chordate NTSS. In the DBD, a methionine at position 16 of the N-terminus was non-chordate-specific, while two amino acids inserted at positions 33–34 of the N-terminus were chordate-specific, These differences which are conserved, support the notion that TR genes duplicated independently in non-chordate and chordate species.
That the JP3 conserved in all invertebrate TRs are also conserved in vertebrate TR genes support the notion that the vertebrate and invertebrate TR orthologue genes originated from a common ancestor gene. Further, that the four JPs are conserved in both invertebrate and vertebrate TR orthologue genes suggest that the gene organization of vertebrate TR genes is ancient and has been maintained through out evolution of TRs.
GST pull-down experiments showed that SmTRs exhibits similarity to vertebrate TR proteins as they both can form a heterodimer with RXR (SmRXR1). RXRs have been characterized in other invertebrates such as Mollusca and Arthropoda [29, 30]. The formation of SmTRs with SmRXR1 indicates that other invertebrate TRs can possibly form a heterodimer with RXR. The ability of vertebrate NR to bind to a DNA element on a target gene was described as the 1–2–3–4–5 rule [31, 32]. Vertebrate TRs are known to bind to half-sites as a monomer, to DR0 as a heterodimer with RXR  and to DR4 as a homodimer or heterodimer [32, 34–43]. The binding of the TR monomer or homodimer is weak, which is due to a rapid dissociation of the TR-TRE complex . Our EMSA show that SmTRα can bind to a half-site as a monomer and bind to DR0-DR5 as a homodimer. The results suggested that TR gained the ability to bind to conserved half-site repeats in a common ancestor, but did not subsequently evolve a distinct specificity as regards spacing between half sites. Although the DBD sequence between SmTRα and SmTRβ are highly similar, SmTRβ showed weak binding to the DNA elements compared to that of SmTRα. This suggests that other domains may have a role in determining the ability of SmTRβ to bind to the DNA element, such as has been shown for another schistosome nuclear receptor, SmNR1 . Although both SmTRs could form a heterodimer with SmRXR1 as determined in a GST pull-down assay, SmTRα/SmRXR1 or SmTRβ/SmRXR1 did not bind to the DNA elements tested. This may due to the flanking or spacing of nucleotides between the HRE, as it is known that these nucleotides also determine the ability of the protein to bind to it. Identification of the HRE in a target gene will help to understand the evolution of TR DNA binding properties. Mammalian TRs are ligand-dependent transcription factors, they repress basal transcription through association with a variety of corepressors in the absence of T3. A structural change occurs when T3 binds to the TR that results in the release of natural corepressors and results in the recruitment of coactivators to activate gene transcription . Determination of whether invertebrate TR can bind to T3 will help to understand the evolution of the thyroid hormone pathway.
We have identified ortholouges of TR in various invertebrate phyla. Sequence analysis demonstrates that there is a 'N-terminal signature sequence' (NTSS) located in the A/B domain -(N-terminal region) specific to TRs. Phylogenetic analysis of conserved DBD sequences showed that TR orthologues originated from a common ancestor of the Bilateria which underwent gene duplication independently in the Protostomia and Deuterostomia. Using the schistosome TR orthologues as representative of the invertebrate TR genes, we have demonstrated that they can form heterodimers with RXR and bind as monomers and homodimers to consensus vertebrate DNA half sites and the direct repeat of the half sites DR0 to DR5.
cDNAs containing the entire open reading frame (ORF) of two S. mansoni TRs (SmTRα and SmTRβ) were isolated by a PCR strategy using a S. mansoni paried adult worm cDNA library (pBluescript SK (+/-) phagemid) pool as template DNA. The PCR primers for one end (either 5' or 3' end) were designed according to a fragment encoding the previously identified DBD region of each gene . The primer for the other end (either 5' or 3' end) was a vector universal primer (M13-Rev and T3, or M13-For and T7 primers). PCR products were separated on 1.2% agarose gels, ligated into pCR2.1 TOPO vector (Invitrogen) and sequenced. After the correct fragments were identified, the cDNA sequence containing the 5' UTR, ORF and 3' UTR were obtained by PCR. Each cDNA was shown to be related to a single mRNA species by sequencing the PCR products obtained from single-stranded cDNA using primers located within the 5'UTR and 3'UTR of each gene.
Whole genomic sequences (WGS) were extracted from the GenBank public ftp site  and imported into the StarBlast program (DNASTAR) to build a local database  which was searched by tblastn using the sequence of the DBD of SmTRα as the query. Any sequence that contained a zinc finger structure of the DBD (Cys-X2-Cys-X13-Cys-X2-Cys or Cys-X5-Cys-X9-Cys-X2-Cys) was retained. Sequence walking was carried out to assemble the contigs. Website databases of GenBank (nr, EST_human, EST_mouse and EST_other databases) Genbank blast , European Bioinformatics Institute  and Swiss-Prot  were also mined by tblasn or blastp using the same query sequence as above .
BAC library screening and BAC DNA sequencing
S. mansoni BAC clones containing SmTRα and SmTRβ were identified by screening S. mansoni SmBAC1 or CHOR-1 BAC library with methods previously described . For BAC DNA sequencing, the BAC clone was grown in 100 ml LB medium (12.5 μg/ml choramphenicol) and the BAC DNA was purified using Plasmid Midi kit (Qiagen) and sequenced on an ABI-377 automatic sequencing machine.
Phylogenetic tree construction
Phylogenetic trees were constructed from deduced sequences of the DBD and the sequence of DBD plus LBD, respectively. Sequences were aligned with ClustalW . Phylogenetic analysis of the data set was carried out using Maximum Likelihood method under Jones-Taylor-Thornton (JTT) substitution model  with a gamma distribution of rates between sites (eight categories, parameter alpha, estimated by the program) using PHYML (v2.4.4))  with support values obtained by bootstrapping a 100 replicates. The same data set was also tested by Bayesian inference using MrBAYES v3.1.1 with a JTT amino acid replacement model + gamma rates . The trees were started randomly; four simultaneous Markov chains were run for 5 million generations for the DBD data set and 3 million generations for the DBD+LBD data set, respectively. The trees were sampled every 100 generations, the Bayesian posterior probabilities (PPs) were calculated using a Markov chain Monte Carlo (MCMC) sampling approach implemented in MrBAYES v3.1.1, with a burn-in value setting at 12,500 for DBD data set and 7,500 generations for the DBD+LBD data set, respectively.
cDNAs encoding part of the hinge region plus the LBD domain of SmTRα (Val739-Glu1115) and SmTRβ (Pro487-Cys847) were inserted into pGEX-4T-1 vectors to form pGEX-SmTRα(LBD) and pGEX-SmTRβ(LBD). cDNA encoding SmRXR1 was previously inserted into pCITE-4a vector to form pCITE-SmRXR1 . E. coli AD 494 (DE3) pLys S competent cells (Novagen) were transformed with pGEX-SmTRα(LBD) or pGEX-SmTRβ(LBD) and the GST fusion proteins were purified by passage over a glutathione-Sepharose column according to standard protocols. pCITE-SmRXR1 was transcribed and translated using the Single Tube Protein System (Novagen) following the manufacture's protocol to produce 35S labeled protein. For pull-down experiments, a 50 μl reaction that contained 2 μl of the in vitro translation reaction, SmTRα(LBD) or SmTRβ(LBD) GST fusion protein, or GST protein (negative control) affixed to glutathione-Sepharose beads (about 2 μg) and binding buffer (50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 10% glycerol, 0.15% Nonidet P40) was used . The reaction was incubated overnight at 4°C and then washed three times with binding buffer. The bound proteins were analyzed by 10% SDS-PAGE and autoradiography.
Electrphoretic mobility shift assay (EMSAs)
cDNA encoding SmTRα, SmTRβ and SmTRα(Gln182-Ala288) (containing 20 aa at the 5' end of the DBD, DBD and 40 aa at the 3' end of the DBD) was inserted into pCITE-4a vector to form pCITE-SmTRα, pCITE-SmTRβ and pCITE-SmTRα(Gln182-Ala288). The protein was produced in vitro using TNT quick coupled transcription/translation system (Promega). The following complementary single-stranded oligonucleotides containing consensus half-sites AGGTCA were synthesized:
half-site: 5'-GTACCGTAAGGTCA CTCGCGT-3',
DR0: 5'-CCGTAAGGTCAAGGTCA CTCG-3',
DR1: 5'-CCGTAAGGTCA CAGGTCA CTCG-3',
DR2: 5'-CCGTAAGGTCA CAAGGTCA CTCG-3',
DR3: 5'-CCGTAAGGTCA CAGAGGTCA CTCG-3',
DR4: 5'-CCGTAAGGTCA CAGGAGGTCA CTCG-3',
DR5: 5'-CCGTAAGGTCA CCAGGAGGTCA CTCG-3'.
Pal0: 5'-CGCAAGGTCATGACCT CG-3' . One strand of each oligonucleotide was annealed after incubation at 100°C for 3 minutes to its complementary oligonucleotide and then labeled with T4 polynucleotide kinase and γ-32P adenosine triphosphate. The binding reactions were incubated on ice for 40 minutes in 15 μl reaction mixture containing 40,000 cpm of probe, 3 μl in vitro translation reaction, 3 μl 5 × buffer (20% glycerol, 5 mM MgCl2, 2.5 mM EDTA, 2.5 mM DTT, 250 mM NaCl, 50 mM Tris-HCl (pH 7.5) and 0.25 mg/ml poly(dI-dC)poly (dI-dC)). The reaction was separated on 6% (v/v) native polyacrylamide gel containing 2.5% glycerol in 1 × TBE buffer at 4°C . Gels were dried, exposed to x-ray film and autoradiographed.
Bacterial artificial chromosome
Ligand binding domain
N-terminal signature sequence
Thyroid hormone receptor
Whole genomic sequence.
This research was supported by NIH grants AI046762 and D43TW006580. We thank the genome sequencing centers for making their data publicly available.
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