Regulation of transcription of the
Dnmt1
gene by Sp1 and Sp3 zinc
finger proteins
Shotaro Kishikawa
1,2
, Takehide Murata
1
, Hiromichi Kimura
2
, Kunio Shiota
2
and Kazunari K. Yokoyama
1
1
Gene Engineering Division, Department of Biological Systems, BioResource Center, RIKEN (The Institute of Physical & Chemical
Research), Japan;
2
Department of Animal Resource Science/Veterinary Medical Sciences, The University of Tokyo, Japan
The Sp family is a family of transcription factors that
bind to cis-elements in the promoter regions of various
genes. Regulation of transcription by Sp proteins is based
on interactions between a GC-rich binding site
(GGGCGG) in DNA and C-terminal zinc finger motifs
in the proteins. In this study, we characterized the
GC-rich promoter of the gene for the DNA methyl-
transferase (Dnmt1) that is responsible for methylation of
cytosine residues in mammals and plays a role in gene
silencing. We found that a cis-element (nucleotides )161
to )147) was essential for the expression of the mouse
gene for Dnmt1. DNA-binding assays indicated that

predominantly in neuronal tissues. The regulation of gene
expression by Sp transcription factors is complex. Although
certain promoters can be activated by either Sp1 or Sp3 in
assays in vivo and are occasionally activated by both Sp1
and Sp3 that act in a synergistic manner [4–6], there are
other promoters that show a definite preference for Sp1 or
Sp3 [7]. Furthermore, Sp3 can function as an activator or a
repressor of transcription, depending on the gene in
question [8,9].
The genes for several mammalian activators and
repressors of transcription have been cloned. The gene
for p300 was first cloned as the gene for an E1A-
associated protein with properties of a transcriptional
adapter [10]. The protein was found later to possess
intrinsic histone acetyltransferase (HAT) activity and
to function as a coactivator in MyoD-, p53-, and SRC-
1-mediated transcription [11,12]. Furthermore, p300
appears to play a critical role in progression of the cell
cycle and the differentiation of cells [11,12].
The methylation of DNA plays a role in the regulation
of gene expression [13,14], genomic imprinting [15] and
inactivation of the X chromosome [16] and it has been
shown to be essential for mammalian development [17,18].
Altered patterns of DNA methylation has been implicated
in tumorigenesis [19]. However, the mechanisms by which
DNA methylation is regulated during development and
tumorigenesis remain largely unknown. Five distinct
families of gene for DNA methyltransferases, designated
Dnmt1, Dnmt2, Dnmt3a, Dnmt3b and Dnmt3L, have been
identified in mammalian cells [20]. Dnmt1 is expressed

promoter [24]. However, specific cis-ortrans-acting
elements involved in the regulation of that promoter
remain to be identified.
In this study, we identified a cis-element located between
nucleotides )161 and )147 that appeared to be activated
independently by Sp1 and Sp3. Moreover, the p300
coactivator appeared to be involved in the Sp3-mediated
activation of the mouse Dnmt1 promoter in somatic cells.
MATERIALS AND METHODS
Cells, plasmids and materials
Mouse NIH3T3 cells and Drosophila SL2 cells were
obtained from the JCRB Cell Bank (Tokyo, Japan) and
from S. Kojima at RIKEN (Tsukuba, Japan). pCMV-Sp1
and pGEX-Sp1 were provided by R. Chiu of the UCLA
School of Medicine (Los Angeles, CA, USA). Plasmids
pPac, pPacSp1, pPacUSp3, pGEX-Sp3 and pCMV-Sp3
were gifts from G. Suske at Philipps-Universita
¨
t(Mar-
burg, Germany). GST–p300 (amino acids 1–596), GST–
p300 (amino acids 744–1571) and GST–p300 (amino acids
1,572–2414) were obtained from Y. Shi of Harvard
Medical School (Boston, MA, USA). Plasmid pCi-p300
was a gift form Y. Nakatani of the Dana Farber Cancer
Research Institute (Boston, MA, USA). DNA fragments
of the mouse Dnmt1 promoter were excised with appro-
priate restriction enzymes (D1 to D5 in Fig. 1A). Each
DNA fragment was inserted into the Nhe1andXho1sites
of pGL3-basic (Promega Co., Madison, WI, USA). The
integrating of all of the above recombinant plasmids was

2962 S. Kishikawa et al. (Eur. J. Biochem. 269) Ó FEBS 2002
Site-directed mutagenesis
Site-directed mutagenesis was performed with a Quick-
Change Site-Directed Mutagenesis Kit (Stratagene,
La Jolla, CA, USA) using various oligodeoxynucleotide
primers (n1 to n10 in Fig. 2D) and a fragment of the
Dnmt1 promoter (nucleotides )220 to +79) as template.
The mutated DNA fragments were subcloned into the
Nhe1andXho1 sites of pGL3-basic (Promega Co.). The
integrity of all of the vectors was verified by sequence
analysis.
Recombinant proteins
Glutathione S-transferase (GST), GST–Sp1, GST–Sp3,
GST–p300 (amino acids 1–596), GST–p300 (amino acids
744–1571) and p300 (amino acids 1572–2414) were prepared
as described previously [25].
35
S-Labeled Sp1 and Sp3 were
synthesized in a TNT Reticulocyte Lysate System (Promega
Co.), according to the manufacturer’s protocol.
Cell culture, transfections and assays of promoter
activity
Mouse NIH3T3 and F9 cells and human HeLa and 293
cells were grown in Dulbecco’s modified Eagle’s medium
(Nissui Pharmaceutical Co., Tokyo, Japan) with 10% fetal
bovine serum (Invitrogen BV, Groningen, the Netherlands)
at 37 °C in a humidified atmosphere of 5% CO
2
in air.
Schneider’s Drosophila SL2 cells were maintained in Shields

luciferase reporter activity in NIH3T3 cells using mutated reporter
constructs. NIH3T3 cells were transfected with the reporter plasmid
D2 or with plasmids that included the sequences n1 through n10 and
luciferase activities were measured, and compared with that obtained
with NIH3T3 cells that had been transfected with reporter plasmid D4
(500 ng). These assays were repeated at least three times and the
standard deviation for each average value is indicated. (D) Nucleotide
sequences obtained by site-directed mutagenesis. Wt, wild-type
sequence; n1 through n10, TT di-nucleotides were introduced, as
indicated, to generate the mutants.
Ó FEBS 2002 Transcription of gene for DNA methyltransferase 1 (Eur. J. Biochem. 269) 2963
Biotech., Uppsala, Sweden). The binding reaction was
performed in 20 lL of buffer that contained 25 m
M
N-2-Hydroxyethylpiperazine-N¢-2-ethanesulfonic acid/KOH
(Hepes/KOH, pH 7.9), 25 m
M
KCl, 5 m
M
MgCl
2
,50m
M
ZnSO
4
,1lg poly(dI-dC), and a nuclear extract or purified
GST-fusion protein. In some cases, competitors or anti-
bodies were added to reaction mixtures which were then
incubated on ice for 20 min. After addition of the
32

AGCTTGCAGGTTGCAGAC-3¢ (reverse direction). PCR
was performed for 35 cycles and products were analyzed
by agarose gel electrophoresis.
Immunoprecipitation and Western blotting
Cell pellets were lysed in RIPA buffer (1· NaCl/P
i
,
1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1%
SDS, 100 lgÆmL
)1
phenylmethanesulfonyl fluoride, 1 m
M
sodium orthovanadate and 2 lgÆmL
)1
aprotinin]. Whole-
cell extracts (500 lg proteins) were incubated with 2 lgof
antibody [anti-Sp1 Ig, anti-Sp3 Ig, anti-(AP-2) Ig, anti-
p300 Ig or nonimmunized rabbit IgG] for 1 h, and then
30 lL of a suspension of protein A/G PLUS-agarose
beads (Santa Cruz) were added. After incubation for 1 h
at 4 °C, immunoprecipitates were gently washed three
times with NaCl/P
i
, boiled and subjected to SDS/PAGE
(7% acrylamide gel). Proteins were electroblotted onto a
poly(vinylidene difluoride) membrane filter and blocked
for 1 h in Blotto A [10 m
M
Tris/HCl (pH 8.0), 150 m
M

itol and 500 lgÆmL
)1
BSA], were incubated at 4 °Cfor1h
andthen30lL of a suspension of glutathione–Sepharose
4B (Amersham Pharmacia Biotech) were added. After
incubation for 1 h at 4 °C, samples were gently washed
three times with NaCl/P
i
, boiled and fractionated by SDS/
PAGE (7% acrylamide gel).
RESULTS
Identification of
cis
-elements that control
expression of the Dnmt1 gene
We subcloned a 2.0-kb DNA fragment that contained the
Dnmt1 promoter region from a mouse genomic clone into
pGL3-basic, a vector that includes a gene for luciferase
without any eukaryotic promoter or enhancer elements. We
then generated a series of 5¢-serial-deletion constructs of the
promoter–luciferase gene for transfections and subsequent
assays of luciferase activity (Fig. 1A). Constructs D1 to D5,
together with the pGL3-basic vector, were used for transient
transfection of NIH3T3 cells in an attempt to identify the
cis-elements of the gene for Dnmt1 and to delineate the 5¢
boundary of the promoter. As shown in Fig. 1A, weak
control of promoter activity was associated with a region of
1827 bp in the upstream region between nucleotides )2000
and )173, with no more than 40% variation in activity. A
large reduction of approximately sixfold in promoter

a 100-fold excess of unlabeled mutant ODN (M1 to M11) to
the reaction mixture, we found that shifted bands were not
eliminated by the unlabeled mutant ODNs M5 through M8.
The nucleotide sequences of these ODNs were com-
pared and the consensus-binding site was defined as the
15-bp sequence 5¢-GGCAAGGGGGAGGTG-3¢ (Fig. 2B),
which we designated the GA motif. To examine whether or
not this sequence is critical for the transcriptional activity of
the Dnmt1 promoter, we synthesized 10 mutant ODNs
(n1 to n10 in Fig. 2D) and introduced them into luciferase
constructs to generate the respective reporter plasmids. We
examined the activity of these luciferase reporters in
NIH3T3 cells and found that only the n5 construct lacked
transcriptional activity (Fig. 2C). Thus, the central GG
dinucleotide in the 15-bp motif seemed to be critical for the
transcriptional activity of the Dnmt1 promoter.
Sp1 and Sp3 bind to the GA motif in the Dnmt1 promoter
To identify the transcription factors that bind to the GA
motif in the Dnmt1 promoter, we looked for transcription
factors in the TRANSFAC database [27]. We failed to
identify known factors that bind to this sequence. However,
we found that both AP-2 and Sp1 bound to sequences that
exhibited strong similarity, namely 0.859 and 0.856,
respectively, to the GA motif. To determine whether Sp1
and/or AP-2 could bind to the GA consensus sequence, we
performed EMSAs in the presence of antibodies against
Sp1, Sp3 and AP-2 (Fig. 3A). The retarded band designed
B1 was shifted even further upon addition of antibodies
against Sp1 (lane 3), while the retarded bands corresponding
to B2 and B3 were shifted further upon addition of

Fig. 3. Sp1andSp3boundtoacis-element in the promoter of the mouse
gene for Dnmt1. (A)
32
P-Labeled probe P3 (1 · 10
4
c.p.m) was incu-
batedwith5lg protein of nuclear extract (NE) from NIH3T3 cells in
the presence and absence of antibodies against Sp1, Sp3 or AP-2. Lane
3, Sp1-specific antibody (2 lg); lane 4, Sp3-specific antibody (2 lg);
lane 5, Sp1-specific and Sp3-specific antibodies (2 lg each); lane 6,
AP-2-specific antibody (2 lg). (B) Chromatin immunoprecipitation
assays. Chromatin immunoprecipitation assays were performed as
described in the text. DNA and proteins were cross-linked with
formaldehyde, and DNA was sheared and immunoprecipitated with
Sp1- or Sp3-specific antibody (2 lgÆmL
)1
each). After reversal of cross-
links, DNA was amplified with primers specific for the promoter
region of the Dnmt1 gene. Products of PCR were resolved by agarose
gel electrophoresis. The arrowhead indicates the amplified DNA
fragment (318 bp).
Ó FEBS 2002 Transcription of gene for DNA methyltransferase 1 (Eur. J. Biochem. 269) 2965
(Fig. 4B). Moreover, the promoter activity of D2 was
further enhanced in the presence of both pPacSp1 and
pPacUSp3 (Fig. 4E). In contrast, the activity associated
with the luciferase reporter construct n5 was not stimulated
by either pPacSp1 or pPacUSp3 (Fig. 4C,D). These results
indicate that both Sp1 and Sp3 enhanced transcription from
the Dnmt1 promoter.
Independent activation of the Dnmt1 promoter

association in vitro (data not shown).
Enhancement by p300 of transcription from the Dnmt1
promoter that is induced by Sp3
The transcriptional coactivator p300 mediates growth arrest
by catalyzing histone acetylation and the subsequent
rearrangement of chromatin [11,12]. Recent reports indicate
that p300 also collaborates with Sp1 or Sp3 to regulate the
expression of the promoter of the gene for p21
Waf1/Cip1
[28,29]. Therefore, we examined the effect of p300 on the
promoter activity of the Dnmt1 gene in the presence of
pCMV-Sp1 and of pCMV-Sp3 in NIH3T3 cells. As shown
in Fig. 6, cotransfection with pCi-p300 and pCMV-Sp3
Fig. 4. Activation of transcription from the Dnmt1promoterbySp1andSp3inDrosophila SL2 cells. SL2 cells were transfected with 500 ng of the
Dnmt1 reporter plasmid D2 (A,B,E) and the reporter plamid n5 without GA motif (C,D) and the indicated amounts of pPacSp1 (A,C), pPacUSp3
(B,D) or both pPacSp1 and pPacUSp3 (E) (each 500 ng) and then luciferase activities were measured. The total amount of the plasmid DNA
(pPacSp1 or pPacUSp3) was adjusted to 1 lg with pPac (no insert). Assays were repeated at least three times and the standard deviation for each
mean value is indicated.
2966 S. Kishikawa et al. (Eur. J. Biochem. 269) Ó FEBS 2002
enhanced the reporter activity controlled by the Dnmt1
promoter, but cotransfection of pCi-p300 with pCMV-Sp1
did not. The extent of activation was much higher than that
obtained with pCi-p300 and with pCMV-Sp3, indicating
that p300 enhanced the promoter activity of the Dnmt1gene
that was induced by Sp3, but not by Sp1. Further studies of
transactivation using a GAL4 fusion with p300 and the
dominant negative form of p300 are required for a full
understanding of the molecular mechanism of this phe-
nomenon.
Sp3 interacts with the C-terminal region of p300

presumably, compensate for the absence of a TATA box
and a CAAT box, and they often have an unusual high
GC-content [1]. The Dnmt1 gene is also a housekeeping
Fig. 5. Binding of Sp1 and Sp3 to the cis-element in the promoter of the
Dnmt1 gene. (A) EMSAs of GST-Sp1 and GST-Sp3 fusion proteins
with the P3 probe. Indicated amounts of GST-Sp1 (onefold to 50-fold
excess) were added to a reaction mixture that included 0.1 lgofGST-
Sp3 and the P3 probe (0.2 nmolÆmL
)1
). (B) Relative binding of Sp1
and Sp3 to P3 in EMSA. The results in (A) are summarized as relative
DNA-binding activity (%). The total intensity of P3 probe on a
reaction mixture for EMSAs was taken arbitrarily as 100%. (C) Sp1
and Sp3 do not form a stable complex in NIH3T3 cells. Immuno-
blotting of Sp1 in the immunoprecipitates derived from 500 lgprotein
of whole-cell extracts of NIH3T3 cells with Sp3-specific antibody
(2 lgÆmL
)1
). Sp1 did not form a complex with Sp3 in NIH3T3 cells.
Input: this lane was loaded 50 lg protein of whole-cell extracts.
Fig. 6. Enhancement of the Dnmt 1 promoter activity upon cotransfec-
tion with p300- and Sp3-expression plasmids. NIH3T3 cells were
transfected with 0.5 lgoftheDnmt1 gene reporter plasmid D2 (see
Fig. 1A) plus 0.5 lg of pCMV-Sp1, pCMV-Sp3 or/and pCi-p300 and
luciferase activity was measured in each case. Total amounts of DNA
(pCMV-Sp1, pCMV-Sp3 and pCi-p300) were adjusted to 2 lgwith
pBSII KS(+). The assay was repeated at least three times and the
standard deviation for each value is indicated.
Ó FEBS 2002 Transcription of gene for DNA methyltransferase 1 (Eur. J. Biochem. 269) 2967
gene [24]. However, details of the cis-elements in its

genes, such as housekeeping genes for tissue-specific and cell
cycle-regulated proteins [3]. Moreover, Sp proteins are
involved not only in activation but also in repression. We
studied the effects on the expression of the Dnmt1geneby
Sp1 or Sp3, which bound to the similar elements (Fig. 3).
The two proteins are found in the same cells and are
indistinguishable in terms of DNA-binding specificity
(Fig. 5A,B), and both proteins bound independently to
the GA motif (Fig. 5C). All Sp proteins contain three zinc
fingers close to the C-terminus, with glutamine-rich domains
adjacent to serine/threonine structures in the N-terminal
region. Sp1, Sp3 and Sp4 are more closely related to each
other than they are to Sp2 [3]. The homology among the
zinc fingers of all known Sp proteins is close to 90%, but,
the homology among entire sequences is close to 40%.
In the transcriptional activation of the Dnmt1 gene, both
Sp1 and Sp3 play a critical role (Fig. 4) via binding to the
same cis-element (GA motif) and the binding of each is
independent of the other (Fig. 5). A competition experiment
in vitro with the GA motif demonstrated that each factor is
able to replace the other in terms of binding to DNA.
The growth characteristics of Sp1-deficient embryonic
stem cells (ES cells) are normal and such cells can be induced
to differentiate [30]. Nevertheless, Sp1 is essential for normal
mouse embryogenesis and the development of Sp1-knock-
out embryos is severely retarded, with death occurring
around day 11 of gestation. Thus, Sp1 appears to be a
transcription factor whose function is essential after day 10
of development. Other Sp proteins, such as Sp3, might be
able to compensate, at least in part, for the loss of Sp1

incubatedwith2.0lg of each GST–p300 mutant, as indicated (lanes
3–5), or with 2.0 lg GST alone (lane 2). Lane 1, one tenth of input
35
S-labeled Sp3. After electrophoresis, radiorabeled protein was
detected by autoradiography. The shaded boxes of p300 indicate the
C/H1 domain, C/H2 domain and C/H3 domain [10].
2968 S. Kishikawa et al. (Eur. J. Biochem. 269) Ó FEBS 2002
Fig. 3A). It has been suggested that two small isoforms of
Sp3 might act as repressor molecules with full-length Sp3
acting as an activator [3,9]. Sp3 acts as a transcriptional
activator at many promoters, as does Sp1 [5,32]. In studies
of other promoters such as the uteroglobin gene [8],
monocyte chemoattractant protein-1 gene and ornithine
decarboxylase gene [7,33], however, Sp3 was found to be
inactive or to act as only a weak activator or as a repressor
of Sp1-mediated transcription.
The most obvious differences between Sp1 and Sp3 are
the presence of a potent inhibitory domain in Sp3 [34]. The
relative abundance of Sp1 and Sp3 allows the fine tuning of
the regulation of gene activities. In endothelial cells that
contain high levels of both Sp1 and Sp3, the ratio of Sp1 to
Sp3 is higher than in nonendothelial cells [35]. In primary
keratinocytes, levels of Sp3 exceed those of Sp1. The ratio of
Sp3 to Sp1 is inverted when these cells differentiate in vitro.
In differentiating keratinocytes, only Sp3 enhances the
activation of the promoter of the gene for p21
Waf1/Cip1
[36].
A change in the ratio of Sp1 to Sp3 also occurs when C2C12
myocytes are cultivated under hypoxic conditions. Hypoxia

through
binding with p300, as such motifs might bind Sp1 and Sp3.
Thus, Sp3 might regulate the TSA-dependent activity of the
promoter. We showed that Sp3 might associate with the
C-terminal region of p300 by direct binding (Fig. 7B). This
region is similar to the region to which GATA-1, E2F and
p53 also bind [10]. Thus, regulation by Sp1 and Sp3 of target
genes might be involved in the cell cycle. Furthermore, the
activity of p300 is dependent on gene dosage during early
embryogenesis. Thus, it is possible that Sp3 might compete
for binding to DNA with Sp1-like proteins and Kru
¨
ppel-
like factors via interactions with p300 at different phases of
the cell cycle in somatic cells. In conclusion, we propose that
the nucleotide sequences to which Sp1 and Sp3 bind are
similar and binding of these factors is independently
regulated by different coactivators in a cell-cycle-dependent
manner. The distinct functions of Sp1 and Sp3 in the
regulation of expression of the Dnmt1geneduringthecell
cycle remain to be clarified.
ACKNOWLEDGEMENTS
The authors thank Drs G. Suske, R. Chiu, Y. Shi, Y. Nakatani,
S. Kojima, H. Ugai, C. Jin, J. Song and A. Wolff for plasmids, reagents
and valuable discussions. This work was supported by the Special
Coordination Funds of RIKEN, by grants from the Ministry of
Education, Science, Sports, Culture and Technology of Japan (to
K. K. Y) and a grant from the Program for Promotion of Basic
Research Activities for Innovative Biosciences (to K. S).
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