From UPR 9023 CNRS-Centre CNRS-INSERM de Pharmacologie-Endocrinologie-141, rue de la Cardonille, 34094 Montpellier Cedex 05, France and ¶ Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire SP2 8BJ, United Kingdom
Received for publication, February 20, 2001
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ABSTRACT |
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ZAC is a recently isolated zinc
finger protein that induces apoptosis and cell
cycle arrest. The corresponding gene is imprinted maternally through an unknown mechanism and maps to 6q24-q25, within
the minimal interval harboring the gene responsible for transient
neonatal diabetes mellitus (TNDM) and a tumor suppressor gene involved
in breast cancer. Because of its functional properties, imprinting
status, and expression pattern in mammary cell lines and tumors,
ZAC is the best candidate so far for both disease conditions. In the present work, we delineated ZAC genomic
organization and mapped its transcriptional start site. It is
noteworthy that the ZAC promoter localized to the CpG
island harboring the methylation imprint associated with TNDM and
methylation of this promoter silenced its activity. These data indicate
that the methylation mark may have a direct effect on the silencing of
the ZAC imprinted allele. Our findings further strengthen
the hypothesis that ZAC is the gene responsible for TNDM
and suggest a novel mechanism for ZAC inactivation in
breast tumors.
The study of imprinted loci is of particular interest in the
context of the coordinated regulation of neighboring genes on the
megabase scale (1). Moreover, imprinted genes are frequently involved
in developmental processes, and loss of imprinting results in a disease
condition in many cases (2). The number of imprinted genes is limited
(nearly 40 have been identified in human or mouse (37)), and the
mechanisms underlying imprinting are as yet poorly understood.
Recently, a novel imprinted locus was mapped to human chromosome
6q24-q25 by different strategies. Kamiya and co-workers (3) used
restriction landmark genomic scanning to isolate genomic sequences
differentially methylated on genomes of maternal and paternal origin,
while Gardner and co-workers (4) determined the minimal interval
harboring the imprinted gene responsible for transient neonatal
diabetes mellitus
(TNDM).1
TNDM is a rare genetic form of diabetes. It is a
developmental disease of insulin production (5) predicted to arise from a defect in pancreatic We recently reported the cloning and functional characterization of
ZAC, which encodes a novel zinc finger protein
inducing apoptosis and cell cycle arrest
(21-23). ZAC was isolated independently by Abdollahi and
co-workers (24, 25) in a search for genes in which expression is lost
in an in vitro model of cell transformation, hence the name
LOT1 for lost on
transformation. Interestingly, ZAC/LOT1 was found to map to 6q24-q25 (22, 25),
a chromosomal region known to harbor a tumor suppressor gene for many
types of solid tumors, including breast and ovary tumors and melanoma (26). Because of its functional properties, chromosomal localization, and loss of expression in a model of cell transformation, we
hypothesized that ZAC may be the tumor suppressor gene on
6q24. ZAC is not inactivated according to the two-hit
hypothesis proposed by Knudson (38) for the retinoblastoma
susceptibility gene. In contrast, we showed that ZAC is
expressed in normal mammary epithelial cells and that 60% of mammary
tumor-derived cell lines display a complete loss of ZAC
expression (27). The remaining 40% of mammary epithelial cell lines as
well as some unselected primary breast tumor samples displayed a
down-regulation of ZAC expression. Interestingly, ZAC expression could be reinduced by treatment of some cell
lines with azacytidine, an inhibitor of DNA methyltransferase,
indicating that methylation of the ZAC promoter may
critically regulate its expression. In this context, we undertook the
isolation and characterization of ZAC gene to elucidate its
imprinting mechanism and pave the way for future studies aimed at
testing the actual involvement of this gene in TNDM and breast cancer.
RACE--
Rapid amplification of the ZAC cDNA 5' end was
performed from placenta poly(A)+ RNA using the Marathon cDNA
amplification kit (CLONTECH, Palo Alto, CA)
according to the manufacturer's instructions, except that RT was
performed with ZAC-specific primers: 5'-GTTGGGGTCGTGGGTCTGG-3'
and 5'-GTCCTTCTTCCCACACTCCTCACAC-3'. RT products were amplified
with AP1 primer and different ZAC-specific primers: R1
(5'-GCCATTTAAGCACAAACAGAACGAT-3'), R3
(5'-TGACAGGGAACATCTGCTGCGA-GG-3'), R5 (5'-TGGTCCCATTAGGTTTCTGTCG3-'),
R6 (5'-TAAGTGAGGTACAGATGAGTTTCAGATGTG-3'), and R7
(5'-CGTCCGTCCGTCCGTC-3') using the Advantage cDNA PCR kit (CLONTECH). For AP1-R1 and AP1-R2 primer pairs, a
nested PCR was subsequently performed with AP2 and R2
(5'-TATAGCTGGGGCATGTCCTGGGTCC3-'), or R4
(5'-GACCGAGTCCTCCCAGAAGTTTGTC-3'), respectively (see Fig. 1 for
primer locations). PCR products were digested with NotI, subcloned into pBS (NotI-EcoRV), and sequenced.
RPA and RT-PCR--
Total RNAs were prepared from mammoplasty
reduction tissues, cell lines, and placental tissues (23). Pituitary
gland poly(A)+ RNA, human fetal liver, and human kidney total RNAs were
from CLONTECH, and human total ovary RNA were from
Research Genetics, Inc. (Huntsville, AL).
RPA was performed as previously described (27). The RPA
antisense ZAC probe was made by T7 in vitro transcription of
pBS-3'5'-876 (see below) digested with NheI. A positive
in vitro T3 transcript sense control was made from the same
plasmid digested with NotI. 50 µg of total RNA or 0.5 µg
of poly(A)+ RNA were hybridized overnight at 56 °C with 2 fmol of
gel-purified antisense ZAC probe and treated with RNase A/T1. Protected
fragments were analyzed on a 5% acrylamide, 8 M urea gel.
RT was performed from 0.5 µg of poly(A)+ RNA or 1 µg of
total RNA with random primers as described previously. 30 cycles of PCR
were performed on 0.2 (pituitary) or 2 µl (other tissues) of
RT product using P1 (5'-GCAGCCGTGCTCACAGCTCAG-3') and P2
(5'-CCAAAGGCCATTTTGTTGGGGTCG-3') oligos (see Fig. 1 for primer
locations). Bands were agarose gel-purified, subcloned into pGEM-T
(Promega), and sequenced.
Cell Culture and Transfection--
Breast cancer cell lines
CAL-51 and MDA-MB453 were grown in DMEM (Life Technologies,
Inc.) supplemented with 10% fetal bovine serum. Cells were
transfected by electroporation with 2 µg of plasmid DNA for 3 × 106 cells, and a luciferase assay was performed as
described previously (21) using
Details on the construction of the different plasmids are available
upon request. A SmaI-StuI 876-bp fragment
corresponding to PAC 340H11 nt 53704-52829 was isolated from a human
bacterial artificial chromosome (BAC) genomic clone (23) and
subcloned into a pGL3 luciferase reporter vector (Promega, Madison, WI) in sense (5'3'-876) and antisense (3'5'-876) orientations relative to
ZAC. From the SmaI site, serial deletions were
performed either by restriction digestions or PCR (in this case,
inserts were sequence-verified).
pGL3-5'3'-876 plasmid was in vitro methylated with
SssI (CpG methylase, which nonspecifically methylates
all CpG dinucleotides) or AluI methylase (which methylates
at AluI sites) from New England Biolabs (Beverly, MA). The
efficiency of in vitro methylation was confirmed by
resistance to cleavage by the methylation-sensitive restriction enzymes
(NotI and HpaI for SssI methylation
and AluI for AluI methylation; not shown). We
also checked that methylase treatments did not induce any alteration of
the plasmid DNAs other than epigenetic; bacteria-transformed methylated
DNAs had a promoter activity as strong as their nonmethylated
counterparts (not shown).
The mechanism responsible for ZAC
imprinting has not yet been determined. The minimal region for TNDM is
covered by clones 468K18, 340H11, 197L1, 3B11, 83M4, and 91J24.
Sequence examination revealed the presence of several CpG islands of
which one (CpG2) is differentially methylated on the paternal and
maternal alleles (4).2 Until now, the isolated most
5' exon of ZAC was located ~70 kb centromeric from CpG2.
In the present report, we used the 5' RACE technique to isolate the
ZAC most 5' exons. Using primers annealing to exon IX or
VII, we could extend the 5' ZAC sequence through different
exons to a CpG-rich region (Exon I). We determined the exon/intron
organization of the ZAC gene by aligning the sequences of
the RACE clones with NT002260 assembled from PACs 197L1,
340H11, and 468K18. The ZAC gene comprises 9 exons, with
exon VIII harboring the translation start site (Fig.
1). This gene organization was confirmed
by RT-PCR of total RNA isolated from different tissues including
mammary gland and pancreas using primers in exon I and IX (Fig.
2). In addition, alternative splicing of
exons II, IV, V, and VIII and the use of alternative splice sites for
exons IV and VII were detected. Despite the significant abundance of the various alternatively spliced isoforms of the ZAC 5'
untranslated region, their relevance remains elusive at this
point. By contrast, we recently showed that splicing of exon VIII
(first coding exon) modulates the functional properties of the
corresponding translation products (23). Of the 50 RACE clones
sequenced, 35 were incomplete, but 15 had their 5' ends into CpG2.
There were three groups of those RACE clones: 7 were incomplete and had
very short 5' ends extending only 10-50 nt into exon I, 7 extended
between nt 52937 and 52907 of 340H11, and 1 RACE clone (the longest)
extended to nt 53070 of 340H11 (note that ZAC is antisense
to 340H11). It was impossible to further extend this 5' end by using
primers annealing to exon IV, III, or I. During the course of this
study, Hamilton's group (25) corrected the sequence of the
human LOT1/ZAC sequence (U72621), which now extends into the
same CpG island to nt 52879 of 340H11. To determine the 5' boundary of
exon I, we performed RNase protection assays using a probe
corresponding to nt 52829-53306 of 340H11, covering part of exon I on
its 5' end. Pituitary and mammary gland RNAs gave 2 major protected
fragments of 95-105 nt, corresponding to a 5' end between nt
52934-52925 of 340H11 close to the start sites given by the RACE
clones extending to nt 52937-52907 of 340H11 (Fig.
3). Two weak, longer protected fragments
could be detected around 240-250 nt corresponding to the start
site given by the longer RACE clone (nt 53070 of 340H11). No protected
fragment was detected in yeast RNA or in RNA from the ZAC
non-expressing cell line MDA-MB231. All of these data predicted a
length of ZAC cDNAs between 2.9 and 3.6 kb in agreement with the size of the mRNAs we described previously (27).
INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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-cell maturation (6, 7). Most TNDM cases are
sporadic, but familial cases also exist. The heritable forms of the
disease are paternally inherited (8-10). Several cases of TNDM were
reported to be due to paternal uniparental disomy of chromosome
6 (11-13) or partial trisomy of chromosome 6q with duplication of the
paternal genome (14-17). Duplications (15) and interstitial deletions
(18) of the same region of the maternally inherited chromosome 6 are
not associated with the disease. These findings strongly suggest that
TNDM results from the overexpression of a paternally expressed,
maternally imprinted gene on chromosome 6q. Using polymorphic markers
and linkage analysis, the gene responsible for TNDM was localized between markers D6S308 and D6S310 (19, 20). Further studies identified
a minimal region containing the gene responsible for TNDM (4). The TNDM
locus is 550 kb in length and harbors several CpG islands, of which one
(CpG2) is methylated on the maternal allele and unmethylated on the
paternal one (4).2 The
importance of this CpG island in the etiology of TNDM is further
underlined by the discovery that a limited number of patients do not
display cytogenetic alterations but rather a defect in the methylation
pattern of CpG2 (4). ZAC, encoding a novel zinc finger
protein recently isolated in this laboratory (see below) is localized
in this region, and Kamiya and co-workers (3) have demonstrated that
ZAC is maternally imprinted in several fetal and adult
tissues. Its functional properties (induction of cell cycle arrest and
apoptosis) are compatible with a role in development and
differentiation, and we hypothesized that overexpression of
ZAC may be responsible for TNDM.
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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-galactosidase to standardize for
transfection efficiency.
RESULTS
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
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DISCUSSION
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Fig. 1.
Genomic organization of
ZAC. Sequencing of RACE clones indicated the
presence of 9 exons, for which the sequence coordinates are given
according to the numbering of PACs 340H11 and 468K18 (ZAC is
antisense to these published sequences): I, 340H11 nt
53070-52754; II, 340H11 nt 29833-29799; III,
340H11 nt 3642-13571; IV, 40H11 nt 0949-10822,
10894-10822, 10876-10822, or 10862-10822, corresponding to
alternative splice acceptor sites; V, 340H11 nt 9967-9844;
VI, 340H11 nt 9482-9451; VII, 340H11 nt
5244-5133, 5220-5133, 5206-5133, or 5206-5137 depending on the use
of alternative acceptor and donor splice sites); VIII,
468K18 nt 130411-129936; and IX, 468K18 nt 124614-122253.
As there were several transcription start sites (see text and Fig. 3),
the size of exon I varied between 160 and 320 bp. Acceptor and donor
sites were in good agreement with consensus splice sites (not shown).
Exons II, IV, V, and VIII are alternatively spliced (indicated by an
asterisk). The translation start site is located in exon
VIII. The CpG island is indicated as well as the location of the
primers used for RACE (R1-R7) and RT-PCR (P1 and
P2). The scale bar concerns the exons only. The
sizes of the larger introns are indicated.
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Fig. 2.
RT-PCR analysis of ZAC expression in
different tissues. P1 and P2 primers (see Fig. 1 for locations)
were used to amplify ZAC cDNAs. The ZAC non-expressing MDA-MB231
mammary tumor cell line together with RT samples were used as negative
controls. Molecular weight markers (MW, 1-kb and 100-bp
ladders) are indicated. PCR fragments were gel-purified and subcloned,
and 40 clones were sequenced. The larger fragments (900-1100 bp)
corresponded to different cDNAs comprising ZAC exons I-IX, with or
without exons II, IV, and V, and different length of exons IV and VII,
depending on the use of alternative splice sites (see legend of Fig.
1). The smaller fragments (400-600 bp) corresponded to the larger ones
without exon VIII. Intermediate fragments (800 bp) corresponded to PCR
artifacts.
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Fig. 3.
Mapping of the ZAC
transcription start site. Different RNA preparations from
ZAC-expressing (pituitary, mammary gland, CAL-51 mammary cancer cell
line) and non-expressing (MDA-MB231 cell line) tissues were used
together with yeast RNA negative control and an in vitro
sense transcript positive control. Lengths of different probes and
control protected fragments used in this experiment, including the ones
shown here, are indicated on the left. Hybridization of the
probe with pituitary and mammary gland RNAs gave different protected
fragments after RNase treatment (indicated by
arrowheads): two weak ones around 240-250 nt,
corresponding to the longer 5'RACE clone; and two stronger and shorter
ones (95-105 nt), corresponding to the sequence of 7 RACE clones.
Interestingly, CAL-51 RNA gave the same long weak protected fragments
but only one of the two shorter ones (105 nt).
We next investigated whether the region upstream of the
potential transcription start sites had a promoter activity. We
subcloned a 876-bp genomic fragment corresponding to nt 53704-52829 of
340H11, in sense (5'3'-876) and antisense (3'5'-876) orientations
relative to ZAC exons, into the pGL3basic reporter gene.
Luciferase activity was measured in CAL-51 (ZAC+ cell line)
(not shown) and MDA-MB453 (ZAC cell line) transfected
cell lines. As shown in Fig.
4A, this fragment (5'3'-876)
contained a promoter activity directed toward ZAC exons,
whereas the fragment in the reverse orientation (3'5'-876) was devoid
of such activity. The results in CAL-51 cells were similar, except that
pGL3-C had a 4-5-fold higher activity than in MDA-MB453
(105 ± 7-fold induction over pGL3basic) and 5'3'-876 a slightly
weaker activity (10 ± 1, compared with the MDA-MB453 value,
30 ± 2) (not shown). Using deletion mutants, we confirmed the RPA
experiments by showing that the minimal promoter was located between nt
53020 and 52829 of 340H11 in the minimal 192-bp construct, which
includes the potential start sites at nt 52934-52925 of 340H11. This
promoter is TATA-less and GC-rich, which is in agreement with the
multiple transcription start sites we detected.
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As we found a promoter activity in CpG2 directed toward
ZAC, we next investigated whether this promoter activity was
modulated by methylation. We used SssI methylase (CpG
methylase), which induced the dense methylation of 5'3'-876 (73 Me-C in a CpG context), and AluI methylase, which
methylates 5 ctyosine residues in a GpC context. SssI
methylation completely abolished the promoter activity of 5'3'-876 in
both MDA-MB453 (Fig. 4B) and CAL-51 cells (not shown) in
contrast to AluI methylation, which had no effect (Fig.
4B). Altogether, these data demonstrated that CpG2 contains the promoter controlling ZAC expression and that its
activity is negatively modulated by dense methylation of cytosine in
the CpG context.
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DISCUSSION |
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Among the different epigenetic modifications involved in imprinting, DNA methylation is particularly relevant, as the great majority of imprinted genes examined so far contain differentially methylated regions (DMRs) on the maternal and paternal alleles (28-30). These DMRs have variable locations within different imprinted genes, and their functional role in the silencing of the imprinted allele is not always indisputable. Some DMRs harbor a promoter activity that is regulated by methylation; our data support such a function for the DMR of the TNDM locus. We have shown here that the ZAC promoter resides in this DMR and that in vitro methylation completely abolishes its activity. These data support a model in which the methylation mark on the imprinted maternal allele represses ZAC transcription, whereas the unmethylated CpG2/ZAC promoter drives the expression of the paternal allele. This is the simplest model of methylation-induced monoallelic expression, where the methylation-induced modification of heterochromatin represses gene transcription. A similar mechanism may be postulated for the imprinting of mZac gene, which is also paternally expressed, as a recent study reported that DNA demethylation but not histone deacetylase inhibition reactivates mZac in uniparental (maternal) mouse embryonic fibroblasts (31). Furthermore, the 5' end of mZac resides in a CpG island with maternal allele-specific methylation analogous to the human gene.3
Other DMRs are involved in establishing differential methylation marks at precise locations within imprinted loci and have been named imprinting centers (ICs) (32). The location of the IC controlling the methylation status of the ZAC promoter remains an open question. Several imprinting models have been described. The expression/competition model is exemplified by the Igf2r locus, where the imprinting center is a DMR located within intron 2. This DMR serves as the promoter for the noncoding antisense Air mRNA and governs the expression of Igf2r (1, 28, 32). The genomic structure we report here for ZAC revealed no DMR located within an intron, excluding a model similar to Igf2r. Another imprinting model follows from the well studied IGF2/H19 locus, where DNA methylation controls the activity of an insulator element located between two linked genes, by regulating the binding of the zinc finger protein CTCF (33, 34). No consensus CTCF binding site was noted in the PACs around the ZAC locus, excluding this model for ZAC imprinting. Indeed, it could be that the IC governing ZAC imprinting is integral to the DMR/ZAC promoter, that the sequence context of the CpG island induces differential methylation, or that there is a remote IC.
The candidate gene for TNDM is located on chromosome 6q24 and is maternally imprinted. To date, CpG2 is the only DMR on this locus. Our demonstration that ZAC is physically associated with CpG2, where its promoter is located, further strengthens the hypothesis that ZAC is the TNDM gene. Furthermore, some TNDM patients have neither paternal UPD6 (uniparental disomy of chromosome 6) nor paternal duplication of 6q24 but instead display a methylation defect in CpG2 (35). We can predict that ZAC will be biallelically expressed in these patients. Transgenic mouse models will help to confirm the involvement of ZAC in TNDM. Besides ZAC, the TNDM locus encodes many ESTs, which may correspond to other TNDM candidate genes. One such candidate is HYMAI, a maternally imprinted, apparently noncoding cDNA, which partially overlaps with CpG2, the ZAC promoter and its first exon (36). The reported sequence of HYMAI is sense with regard to ZAC, but according to the annotations of the ESTs used for its cloning it could be antisense. This issue will have to be addressed to find out whether HYMAI encodes a noncoding antisense RNA, as is observed in several imprinted loci, or whether it is co-linear with ZAC and both genes compete for the same promoter.
Because of its antiproliferative properties and chromosomal
location, ZAC is a candidate tumor suppressor gene for
breast cancer. Provided that ZAC expression is monoallelic
in the mammary gland, a single event (the inactivation of the
paternally expressed allele) would be sufficient to completely
inactivate ZAC, supporting a tumor suppressor function for
this gene. The location of the ZAC promoter, which we report
here, paves the way for future studies aimed at resolving this
important issue.
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ACKNOWLEDGEMENTS |
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We thank Gavin Kelsey for critical reading of the manuscript and for sharing data before submission and Anne-Marie Coupe for technical assistance.
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FOOTNOTES |
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* This work was supported by grants from the Centre Nationale de la Recherche Scientifique, La Ligue Nationale contre le Cancer, L'Association pour la Recherche contre le Cancer (ARC), the European Commission (QLG3-CT-1999-00602), and Diabetes UK (RD98/0001627).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.
§ Recipient of predoctoral fellowships from the Ministère de l'Education Nationale, de la Recherche et de la Technologie and from the ARC.
Recipient of postdoctoral fellowships from the Ministère
des Affaires Etrangères and the Fondation pour la Recherche
Médicale.
To whom correspondence should be addressed. Tel.:
33-467 142 963; Fax: 33-467 542 432; E-mail:
varrault@ccipe.montp.inserm.fr.
Published, JBC Papers in Press, April 10, 2001, DOI 10.1074/jbc.C100095200
2 D. J. G. Mackay, unpublished observation.
3 G. Kelsey, personal communication.
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ABBREVIATIONS |
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The abbreviations used are: TNDM, transient neonatal diabetes mellitus; bp, base pair(s); nt, nucleotide(s); kb, kilobase(s); ZAC, zinc finger protein that induces apoptosis and cell cycle arrest; RT, reverse transcriptase; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; DMR, differentially methylated region; IC, imprinting center; RPA, RNase protection assay; PAC, P1 artificial chromosome; EST, expressed sequence tag; Me-C, methyl-cytosine.
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