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J. Biol. Chem., Vol. 277, Issue 51, 49517-49522, December 20, 2002
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From the
Received for publication, September 17, 2002, and in revised form, October 17, 2002
Nuclear receptors are ligand-modulated
transcription factors that transduce the presence of lipophilic ligands
into changes in gene expression. Nuclear receptor activity is regulated
by ligand-induced interactions with coactivator or corepressor
molecules. From a positive hormone response element (pHRE) and in the
absence of hormone, corepressors SMRT and N-CoR are bound to some
nuclear receptors such as the thyroid hormone (T3Rs) and
retinoic acid receptors and mediate inhibition of basal levels of
transcription. Ligand binding results in dissociation of corepressors
and association of coactivators, resulting in the reversal of
inhibition and a net activation of transcription. However, the role of
cofactors on the activity of nuclear receptors from negative HREs
(nHREs) is poorly understood. Here we show that corepressor SMRT can
act as a potent coactivator for T3R Transcriptional regulation is fundamental to the normal
functioning of the cell and is achieved through positively or
negatively acting transcription factors (1, 2). Whereas in some
cases the transcription factors that activate and repress gene
expression are encoded by different genes, increasingly more
transcription factors are now recognized to function both as an
activator and a repressor depending on the nature of the response
element that they interact with and the cellular context (1, 2).
However, the details of how an activating transcription factor can
become a repressor and vice versa is not well understood.
One of the factors that can serve as a transcriptional activator or
repressor depending on the response element and cellular context is the
thyroid hormone receptor
(T3R)1 (3, 4), which belongs
to the nuclear receptor superfamily of ligand modulated transcriptional
factors (for reviews, see Refs. 5 and 6). Recent studies have begun to
uncover the molecular details of this bimodal activity on a positive
hormone response element (pHRE). In the absence of hormone, T3R
associates with corepressor molecules, such as SMRT and N-CoR (7-9),
which assemble a repressive complex that shuts down transcription
(reviewed in Refs. 5 and 6). This is likely to be due the activity of
histone deacetylases, which are recruited to this complex. In the
presence of ligand, this corepressor complex dissociates and is
replaced by a coactivator complex that then activates transcription at
the promoter, which is probably because of the recruitment of histone
acetyltransferases (5, 6). In contrast, at the negative HREs (nHREs),
activation of transcription occurs in the absence of ligand
(e.g. 10), when T3R is expected to be in a complex with
corepressors and coactivators are not expected to be recruited to the
promoter. This is therefore a paradoxical situation. It has recently
been suggested that corepressors may be involved in activating
transcription of genes that are negatively regulated by thyroid
hormone, but the exact mechanisms involved remain to be identified
(11-13).
To gain insight into the molecular details of transcriptional
activation at a nHRE, we have compared the contribution of corepressors to the activities of T3R Cell Culture, Transient Transfection, and Luciferase
Assays--
HeLa and CV-1 cells were maintained in Dulbecco's
modified Eagle's medium supplemented with 5% fetal bovine serum,
antibiotics, and glutamine. The calcium phosphate coprecipitation
method was used to transfect HeLa cells with 0.25 µg of reporter
plasmid, 50-125 ng of expression vector, and pUC18 to a total of 1 µg of DNA/well in a 12-well dish. After 5-8 h of incubation with the precipitates, cells were shocked with 10% glycerol in
phosphate-buffered saline, washed once with phosphate-buffered saline,
and then maintained in Dulbecco's modified Eagle's medium
supplemented with 0.5% charcoal-treated fetal bovine serum in the
presence or absence of T3, (10 Plasmids--
Reporter plasmids 2XT3RE-LUC (8) and
RSV180-LUC (10) and the expression vectors for T3R GST Pull-down Assay--
The production and purification of the
GST fusion proteins and the in vitro interactions between
T3R Mobility Shift Analysis--
Preparation of recombinant T3R T3 Binding Assay--
125I-T3 binding assays were
performed on the in vitro translated wild-type and mutant
receptors as described (16). The wild-type T3R To assess the potential contribution of SMRT and N-CoR to
activation of transcription from a nHRE, we studied the activities of
T3R Because all known activities of T3R We then tested the mutant proteins for their ability to activate
transcription from a pHRE. HeLa cells were cotransfected with the
MHC-CAT reporter, which contains two copies of the MHC T3RE (17). Cells
were cotransfected either with an empty expression vector or with
expression vectors specifying wild-type T3R To determine whether the mutant receptors are altered in their ability
to interact with SMRT and N-CoR, we performed glutathione S-transferase (GST) pull-down experiments. The receptor
interaction domain (RID) of SMRT (8) was expressed as a GST fusion
protein in Escherichia coli (GST-SMRT-(914-1495)),
purified, and used in the GST pull-down assay with cell-free
translated, 35S-labeled wild-type T3R
Corepressor SMRT Functions as a Coactivator for Thyroid Hormone
Receptor T3R
from a Negative Hormone Response Element*
§,,§,,§
Biotechnology Centre of Oslo and the
§ Department of Biology, University of Oslo, Postboks 1050 Blindern, Oslo 0316, Norway and the ¶ Metabolic Research Unit,
University of California, San Francisco, California, 94143-0540
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from a nHRE; N-CoR has a similar but significantly attenuated activity. Mutagenesis of residues in the
hinge region of T3R that block binding of SMRT and N-CoR inhibits
ligand-independent transcriptional activation by T3R from a nHRE.
These mutations also abrogate SMRT-mediated increase in transcriptional
activity by T3R at a nHRE without significantly affecting
ligand-dependent activation at a pHRE. Partial protease digestion coupled to the mobility shift assay indicate differences in
the conformation of T3R-SMRT complexes bound to a pHRE
versus a nHRE. These results suggest that allosteric
changes resulting from binding of T3R to different response
elements, i.e. pHREs versus nHREs, dictate
whether a cofactor will function as a coactivator or a corepressor.
This, in turn, greatly expands the repertoire of mechanisms used
in modulating transcription without the need for expression of new
regulatory molecules.
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from pHREs and nHREs. We found that interaction of corepressor SMRT with T3R is essential for
transcriptional activation at the RSV nHRE (10). Our results suggest
that the interaction of SMRT with T3R on a pHRE is topologically
different from SMRT-T3R interactions on a nHRE, which may
account for these differential effects.
MATERIALS AND METHODS
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7 M). For CV-1
cells, the same procedure was followed except that the glycerol shock
was not performed. Luciferase (LUC) enzyme activities were determined
as described previously (10).
(pSG5-c-ErbA, referred to here as pSG5-T3R) (15), SMRT (7), and
N-CoR (9) have been described. For the generation of the mutant T3R
constructs, single-stranded mutagenic primers were synthesized
corresponding to the amino acids centered around the BstEII
site in the hinge region of
T3R.2 These primers and a
primer corresponding to the SV40 polyadenylation sequence
(residues 1109-1130 in pSG5) were used in PCR with pSG5-T3R as the template, and the amplified fragments were digested with BstEII and BamHI and exchanged with the
corresponding fragment of pSG5-T3R. All mutants were confirmed by
sequencing. For the generation of the GST-SMRT-(914-1495),
pGEX-KG-TRAC2 (7) was cut with XbaI and NotI,
filled in with Klenow polymerase, and religated. To generate
GST-N-CoR-(1873-2453), pCEP-N-CoR (9) was cut with
NotI and BglII (partial), and the fragment was
inserted into the BamHI and NotI sites of pGEX4TI (Promega).
and SMRT or N-CoR were examined by the GST pull-down assay as
described previously (7).
and the conditions for the mobility shift analyses were essentially as
described previously with minor modifications (10). Briefly,
recombinant T3R (25 and 105 ng for the MHC- and RSV-T3REs,
respectively) was incubated with GST-SMRT-(914-1495) (100 ng) for 10 min at room temperature to allow heterodimer formation. The probes and
rest of the DNA binding mix were then added (0.3 µg of
poly(dI-dC) in 5 mM HEPES, pH 7.9, 25 mM
KCl, 6.25 mM MgCl2) and the reactions were
continued at room temperature for 10 min. Increasing amounts of the
indicated protease were then added, and the reactions were incubated at room temperature for an additional 5 or 10 min for chymotrypsin and
carboxypeptidase Y, respectively, followed by immediate loading on a
5% nondenaturing polyacrylamide gel. After electrophoresis, gels were
dried, and bands were visualized by PhosphorImager analysis (Amersham
Biosciences). to facilitate comparison, the RSV-T3RE portion of the
gels were exposed longer to give an intensity of bands approximately
similar to those of the MHC-T3RE portion.
and mutant
receptors translated in vitro using the TNT expression system (Promega) were used in the T3 binding assay, and
Kd values were calculated using the Prism computer
program (GraphPad Software, Inc.).
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from a well characterized nHRE found in the Rous sarcoma virus
long terminal repeat (LTR), termed RSV-T3RE (10). We reasoned that if
SMRT and/or N-CoR had a role in ligand-independent activation from the
RSV-T3RE, mutations that block T3R-SMRT or T3R-N-CoR interactions
should abrogate this activity. To that end, we generated point
mutations within the hinge region of T3R based on previous mutational studies with T3R
and N-CoR that have established the residues important for this interaction (9). We targeted two residues
that are conserved between T3R and T3R within this region,
Ala-174 and His-175, which were changed either to an acidic (M13), an acidic and a nonpolar (M15), a small hydrophobic and a
nonpolar (M17), or two small nonpolar residues (M18) (Fig.
1A). For M19 and M20, we also
substituted an additional residue, Thr-178, with a small hydrophobic
residue, to generate triple mutants similar to those used previously in
studying T3R and N-CoR interactions (9).
View larger version (38K):
[in a new window]
Fig. 1.
Detailed mutational analysis of
T3R hinge region. A, domain
structure of T3R is depicted. The DNA-binding (DBD) and
ligand-binding (LBD) domains are indicated. The sequence of
the conserved corepressor-binding domain in T3R was aligned
with that of wild-type T3R, and the residues in which mutations were
introduced are underlined. For the T3R CoR mutants, only
those residues that have been replaced are indicated. The dissociation
constant (Kd) for each mutant protein and the
standard error (S.E.) is indicated on the right
of the figure. B, ligand-dependent
transcriptional activation by T3R hinge domain mutants. HeLa cells
were cotransfected with the MHC-CAT (0.25 µg) reporter plasmid and
expression vectors encoding wild-type (WT) T3R, the
indicated mutants, or the empty expression vector pSG5 (50 ng of each)
by the calcium phosphate procedure. Cells were either left untreated or
treated with T3 (107 M) and harvested after
18 h, and CAT activities were determined. CAT activity in the
presence of wild-type T3R and T3 is set arbitrarily at 100%. The
results represent the average of at least three independent experiments
with standard deviations shown as error bars.
are modulated by hormone
binding, we first examined the ability of the mutant receptors to bind
T3. Scatchard analysis showed that the dissociation constants of the
mutant receptors were in the range of 0.20 to 8.5 nM, as compared with 0.02 nM for the wild-type T3R. All mutant
receptors are expected to be saturated with hormone in the experiments
described below since an ~12-fold excess of T3 (100 nM)
over the Kd of the weakest binder was used.
Therefore, a deficiency in hormone binding is unlikely to account for
the differential activities of the mutant receptors.
or the various mutants.
After transfection, the cells were either left untreated or treated
with T3 for 18 h, and CAT activities were determined. As shown in
Fig. 1B, wild-type T3R activated MHC-CAT expression
10-fold in the presence of T3. All of the mutants also activated
2XT3RE-LUC (14), which contains two consensus T3REs, ranging between 45 and 70% activity compared with wild-type T3R. These results suggest
that all mutants are functional for transactivation from a pHRE, bind
hormone, and are expressed at levels similar to wild-type T3R.
or its mutants in
the presence or absence of T3. As shown in Fig.
2A, although there was
no significant interaction with GST alone, wild-type T3R displayed
significant binding to GST-SMRT(914-1495) in the absence of T3, which
was lost in the presence of T3. In contrast, all of the mutants
exhibited a significantly compromised ability to bind SMRT either in
the presence or absence of T3. An essentially identical pattern of interaction of the T3R mutants with N-CoR was observed in a similar GST pull-down assay (Fig. 2B).
View larger version (30K):
[in a new window]
Fig. 2.
In vitro interactions between
T3R hinge domain mutants and corepressors SMRT
and N-CoR. A, the C-terminal receptor-interacting
domain of SMRT was expressed as a GST fusion protein
(GST-SMRT-(914-1495)) in E. coli and purified on
glutathione-Sepharose beads. GST-SMRT-(914-1495) or GST alone was then
used in the GST pull-down assay with cell-free translated
35S-labeled T3Rs in the presence (+) or absence (
) of T3
(106 M) as described under "Materials and
Methods." The input levels of 35S-labeled T3R proteins
used in each binding reaction were approximately the same (data not
shown). The gel shown is representative of three independent
experiments. B, same as in A, but
GST-N-CoR-(1873-2453) was used in the pull-down assay.
To assess whether the mutations that disrupt the interaction of SMRT
with T3R have a role in ligand-independent activation from a nHRE,
we performed transient transfection experiments. HeLa cells were first
cotransfected with RSV180LUC (10), which contains the
RSV-T3RE in the RSV-LTR driving expression of LUC, and either an empty
expression vector or an expression vector specifying wild-type T3R
or one of the mutants. As shown in Fig. 3A, whereas wild-type T3R
efficiently activated RSV180LUC in the absence of T3 that
was relieved in the presence of T3, none of the mutants significantly
activated RSV180LUC in the presence or absence of T3.
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The mutants having lost their ability to bind SMRT in vitro
suggested that corepressor interactions may be involved in
ligand-independent activation by T3R from a nHRE and prompted us to
determine whether SMRT could serve as a coactivator for T3R in this
context. To that end, the same transient transfection assay as
described above was performed in the presence of an expression vector
encoding SMRT. Coexpression of T3R and SMRT gave rise to ~5-fold
greater activation of RSV180LUC expression when compared
with expression of T3R alone. SMRT coexpression did not
significantly affect ligand-induced relief of RSV180LUC
activation as it was relieved back to basal levels or lower in the
presence of T3. On the other hand, the mutant receptors did not show
any significant activity in response to SMRT coexpression, even at
higher levels of SMRT expression (Fig. 3A, and data not
shown). This finding is consistent with the significantly diminished
in vitro interactions between the T3R mutants and SMRT in
the GST pull-down assay (Fig. 2A). These data suggest that
SMRT serves as a coactivator for T3R from a nHRE.
In a similar series of experiments, we tested the possible effect of
N-CoR coexpression on ligand-independent activity of T3R from the
RSV180LUC reporter. N-CoR coexpression with T3R resulted
in a modest increase of RSV180LUC expression that was less
than 2-fold compared with the levels achieved in the presence of T3R
alone (Fig. 3B). We did not find any more significant increase in stimulation of T3R activity from RSV180LUC
at a wide range of lower or higher levels of N-CoR coexpression (data
not shown). These results suggest that N-CoR has only a modest effect on the activity of T3R on a nHRE in vivo.
One possible explanation for how SMRT can act as a corepressor for
T3R from a pHRE and a coactivator from a nHRE is that the complexes
formed on these two response elements have different conformations,
resulting in different contributions to the transcriptional initiation
complex. To assess this possibility, we used a combination of the
mobility shift and partial protease digestion assays with a pHRE
(MHC-T3RE) compared with a nHRE (RSV-T3RE). When recombinant T3R
expressed in E. coli was used in the mobility shift assay, a
major shifted band corresponding to the T3R homodimers was formed
with both probes (Fig. 4; also see Refs.
10, 15, and 18). When GST-SMRT-(914-1495) was included in the binding
reaction, an additional band migrating more slowly was formed
corresponding to T3R-SMRT complexes. GST-SMRT-(914-1495) alone did
not bind either probe (data now shown). Both T3R homodimers and
T3R-SMRT complexes were specific as shown by competition studies,
and they contained T3R as indicated by supershift analysis (Refs.
10, 15, and 18 and data not shown).
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To assess whether there are conformational differences between the
heterodimers formed on the two T3REs, the mobility shift binding
reactions were carried out first to allow heterodimeric complex
formation on DNA; these were then subjected to partial proteolysis with
increasing amounts of either carboxypeptidase Y (CarbY, Fig.
4A) or chymotrypsin (Chy, Fig. 4B). As
shown in Fig. 4A, increasing amounts of carboxypeptidase Y
quickly converted the T3R-SMRT complex into a form that migrated
faster, running just above the migration point of the T3R-T3R
homodimers on both response elements (compare lane 2 with
lanes 5-7). However, the faster migrating band formed on
the MHC-T3RE at higher concentrations of carboxypeptidase Y was
resistant to further digestion; this band is also wide, indicating the
presence of more than one polypeptide complex bound to DNA. In
contrast, the band formed upon carboxypeptidase Y digestion on the
RSV-T3RE is a sharp, single-species band in which mobility is clearly
increased in a stepwise fashion as the amount of enzyme is increased
(Fig. 4A, compare lanes 5-7 for the two T3REs).
Similar results were obtained when the experiment was repeated with
chymotrypsin. The addition of increasing amounts of chymotrypsin to the
binding reaction resulted in an increase in the mobility of the
T3R-SMRT complex for both probes (Fig. 4B). However there were differences in the pattern of bands generated and their rate of
appearance. With increasing amounts of chymotrypsin, a band that
migrated faster than the T3R homodimers was formed that was more
resistant to digestion on the RSV-T3RE compared with the MHC-T3RE (Fig.
4B, compare lanes 5-7 between the two panels, lower arrow). In addition, this band was wide for the
MHC-T3RE, as opposed to a tight, single-species band on the RSV-T3RE,
indicating the presence of multiple polypeptides in the complex formed
with the MHC-T3RE. Limited protease digestion of the homodimers alone under the same conditions gave rise to different, faster migrating bands compared with the experiments described above, indicating that
the bands appearing upon proteolysis in the experiments presented in
Fig. 4 are primarily the products of the T3R-SMRT complex (data not shown).
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We have studied the possible role of the corepressors SMRT and
N-CoR on transcriptional activation by T3R from a well characterized nT3RE in the RSV promoter (10). Our results indicate a direct role of
the corepressor SMRT in transcriptional activation by T3R from a
nHRE, whereas N-CoR had a significantly attenuated effect. At
present, the basis for the differences between SMRT and N-CoR on
regulating T3R action from a nHRE are not clear.
This paradoxical finding can be explained by the different
conformations that SMRT assumes on a pHRE (exemplified by the MHC-T3RE in this study) compared with a nHRE (the RSV-T3RE). This is indicated by the fact that the sensitivity of the T3R-SMRT complex to
proteases is different depending on the response element on which it is formed. This is expected to differentially affect the proteins recruited to the promoters, thus giving rise to diametrically opposite
transcriptional outcomes.
This hypothesis is depicted schematically in Fig.
5. In the absence of hormone, when the
T3R-SMRT complex is bound to the MHC-T3RE, it assumes a different
conformation than when bound to the RSV-T3RE. This, in turn, results in
the recruitment of a different collection of polypeptides to the
complex, one that activates the transcriptional initiation complex, and
the other that represses it.
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Recent reports suggested that a putative splicing variant of N-CoR,
N-CoR-I (19), which lacks the N-terminal repressor domain, can act as
an activator for the mouse preprothyrotropin-releasing hormone gene
(TRH) (13), which is known to be negatively regulated by
thyroid hormone. N-CoR-I also inhibits the ligand-independent repression by T3R at pHREs, presumably through competition with the
endogenous N-CoR and SMRT that are involved in this process (27). In
addition, N-CoR and SMRT are involved in basal activation of the
promoters that are negatively regulated by thyroid hormone (11, 12).
This finding was suggested to be due to protein-protein interactions
involving a non-DNA bound T3R, allowing the association of
coactivators with the DNA-bound transcription factor cAMP-response element-binding protein (CREB) at the TSH promoter in the absence of
hormone; the coactivator is removed from the DNA by a hormone-activated T3R, resulting in repression (12).
The findings we have presented here suggest that the effect of SMRT on
T3R activity on a nHRE is direct and that DNA binding by T3R is
required for these activities. Indeed, whereas the nHREs on the TSH
promoter are poorly defined and therefore the negative effects of
T3R action in the presence of hormone are likely to be mediated by
protein-protein interactions, as suggested previously (12), the
RSV-T3RE that is used in our studies is well characterized and is
essential for this activity (7). Furthermore, by using an artificial
construct in which the RSV-T3RE is fused to a minimal promoter driving
expression of the LUC gene, similar affects of SMRT on potentiation of
T3R action is observed.3
Taken together, these findings suggest that there may be two distinct
mechanisms by which a corepressor may mediate transcriptional activation by T3R at a negatively regulated promoter, dictated by
the nature of the cis elements present. One mechanism involves the removal of the corepressors from DNA by the receptor, and the other
involves recruitment of the corepressors to the DNA and assembly of a
coactivating complex. Future work will be needed to define the
components of these complexes and how they activate transcription.
It has recently been shown that coactivators of the nuclear receptor
superfamily to which T3R belongs either recruit or are themselves
histone acetyltransferases; conversely, the corepressors recruit
histone deacetylases (for reviews, see Refs. 5 and 6). It has therefore
been suggested that changes in histone acetylation and subsequent
effects on chromatin structure may be the mechanism through which
cofactors mediate regulation of transcription (for reviews, see Refs.
20-23). It will now be important to determine what the differences are
in the complexes that are formed by T3R and SMRT on the pHRE
versus the nHRE in the absence of hormone and whether they
contain histone acetyltransferases or histone deacetylases.
To our knowledge, this is the first report in which a corepressor is
shown to function as a coactivator that is dependent on DNA binding by
its transcription factor. The role of the allosteric effects of DNA on
the transcription factors that bind to it has been recognized for some
time (for a review, see Ref. 24). The findings we report here extend
the importance of these allosteric effects by demonstrating that even
the cofactors that bind to the transcription factor will be affected,
such that they can function in a diametrically opposite fashion when
tethered to transcription factors bound to different response elements.
The fact that a cofactor previously identified as a corepressor can also function as a coactivator in another context through these allosteric effects greatly increases the repertoire of responses that
the cell can mount to various signals without additional gene
activation or protein synthesis.
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ACKNOWLEDGEMENTS |
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We thank A. Munoz, C. Glass, M. Privalsky, and M. Zenke for generous gifts of plasmids and the members of the Saatcioglu laboratory for critically reading the manuscript.
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FOOTNOTES |
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* This work was supported by grants from the Norwegian Research Council and the University of Oslo (to F. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 47-22854569;
Fax: 47-22854601; E-mail: fahris@bio.uio.no.
Published, JBC Papers in Press, October 17, 2002, DOI 10.1074/jbc.M209546200
2 Sequences are available upon request.
3 H. Berghagen, K. Krogsrud, and Fahri Saatcioglu, unpublished results.
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ABBREVIATIONS |
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The abbreviations used are: T3R, thyroid hormone receptor; pHRE, positive hormone response element; nHRE, negative hormone response element; SMRT, silencing mediator of retinoid and thyroid receptors; N-CoR, nuclear receptor corepressor; RSV, Rous sarcoma virus; LUC, luciferase; GST, glutathione S-transferase; MHC, myosin heavy chain; LTR, long terminal repeat; TSH, thyroid-stimulating hormone (thyrotropin).
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