Enrichment for Histone H3 Lysine 9 Methylation at Alu Repeats in Human Cells*
Yutaka Kondo
and
Jean-Pierre J. Issa
From the
Department of Leukemia, University of Texas M. D. Anderson Cancer Center,
Houston, Texas 77030
Received for publication, April 17, 2003
, and in revised form, April 28, 2003.
 |
ABSTRACT
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The aim of this study was to identify in human cells common targets of
histone H3 lysine 9 (H3-Lys9) methylation, a modification that is
generally associated with gene silencing. After chromatin immunoprecipitation
using an H3-Lys9 methylated antibody, we cloned the recovered DNA
and sequenced 47 independent clones. Of these, 38 clones (81%) contained
repetitive elements, either short interspersed transposable element (SINE or
Alu elements), long terminal repeat (LTR), long interspersed
transposable element (LINE), or satellite region (ALR/Alpha) DNA, and three
additional clones were near Alu elements. Further characterization of
these repetitive elements revealed that 32 clones (68%) were Alu
repeats, corresponding to both old Alu (23 clones) and young
Alu (9 clones) subfamilies. Association of H3-Lys9
methylation was confirmed by chromatin immunoprecipitation-PCR using conserved
Alu primers. In addition, we randomly selected 5 Alu repeats
from the recovered clones and confirmed association with H3-Lys9 by
PCR using primer sets flanking the Alu elements. Treatment with the
DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine rapidly decreased
the level of H3-Lys9 methylation in the Alu elements,
suggesting that H3-Lys9 methylation may be related to the
suppression of Alu elements through DNA methylation. Thus
H3-Lys9 methylation is enriched at human repetitive elements,
particularly Alu elements, and may play a role in the suppression of
recombination by these elements.
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INTRODUCTION
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Post-translational modifications of histone tails play a critical role in
the assembly of heterochromatin, and accumulating evidence suggests that the
pattern of histone modifications specify regulation of gene expression
(1,
2). Acetylation of lysine
residues on histone H3 and H4 usually leads to the formation of an open
chromatin structure, with transcription factors accessible to promoters.
Phosphorylation of serine 10 and acetylation of lysine 14 on histone H3 result
in gene activation (3).
Lys4 methylation on histone H3 localizes to sites of active
transcription, and this modification may be stimulatory for transcription
(4). The different combinations
of histone tail modifications influence transcription by affecting chromatin
structure. Recent studies have shown that methylation at Lys9 on
histone H3 is a marker of heterochromatin and is specifically associated with
inactivation of gene expression
(5). H3-Lys9
methylation is enriched on the inactive X chromosome in women
(6) and at loci silenced in
cancer
(79).
Beyond this, the distribution of H3-Lys9 in human DNA has not been
well characterized.
Alu repeats represent the most frequent repetitive element in the
human genome (10).
Alu elements are
280 bp in length and consist of two similar,
but distinct, monomers linked by an oligo(dA) tract. Presumably, the 1 million
Alu elements that are fixed within the human genome represent the
fraction of insertions that were neutral or at least tolerable functionally.
Alu elements possess an RNA polymerase (pol III) promoter
(11). Despite this, the steady
state abundance of pol III-directed Alu transcripts is usually very
low in tissues and cultured cells indicating transcriptional silencing
(12). However, cellular stress
can dramatically increase the abundance of human Alu RNA
(12), although it is unknown
how and how many Alu elements are induced by stress. Accumulating
evidence indicates that regulation of Alu expression is determined on
many levels, some of which act locally upon individual Alu elements
(13,
14). DNA methylation and
chromatin configuration might each globally repress transcription of this
repetitive sequence family and therefore potentially direct regulation of the
Alu stress response.
Here we performed an unbiased approach to clone targets of
H3-Lys9 methylation using chromatin immunoprecipitation
(ChIP)1 assay and
found that most such clones contain Alu elements. Thus, Alu
expression might be crucially regulated by H3-Lys9 methylation and
associated chromatin remodeling.
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EXPERIMENTAL PROCEDURES
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Cell Lines and Culture ConditionsSW48 cells were grown in
L-15 medium (Invitrogen) plus 10% fetal bovine serum in plastic tissue culture
plates in a humidified atmosphere containing 5% CO2 at 37 °C.
RKO cells were grown in high glucose Dulbecco's modified Eagle's medium
(Invitrogen) plus 10% fetal bovine serum (Intergen). The cells were grown to a
density of 5.0 x 105 to 3.0 x 106 cells per
dish before being harvested for cross-linking experiments. Cell lines were
obtained from the American Type Culture Collection.
5-Aza-dC Treatment of CellsCells were split 1224 h
before treatment. Cells were then treated with either 5-aza-dC, 5
µM (Sigma), or phosphate-buffered saline for 72 h. Media
containing 5-aza-dC or phosphate-buffered saline was changed every 24 h.
Chromatin ImmunoprecipitationThe protocols for ChIP have
been described previously
(15). Briefly, SW48 and RKO
cells are treated with 1% formaldehyde for 8 min to cross-link histones to
DNA. After washing by cold phosphate-buffered saline, the cell pellets are
resuspended in 550 µl of lysis buffer (150 mM NaCl, 25
mM Tris-Cl, pH 7.5, 5 mM EDTA, 1% Triton X-100, 0.1%
SDS, 0.5% sodium deoxycholate) and sonicated for 7 x 8 s. The lysate
(500 µl) is then divided into three fractions; the first and second ones
(230 µl each) are diluted in 260 µl of lysis buffer, and the third one
(40 µl) is used for input control. The first lysate is incubated with 10
µl of anti H3-Lys9 methylated histone H3 antibody (Upstate
Biotechnology) at 4 °C overnight. The second lysate is incubated with
Tris/EDTA buffer (10 µl) at 4 °C overnight as a negative control. To
collect the immunoprecipitated complexes, protein A-Sepharose beads (Amersham
Biosciences) are added and incubated for 1 h at 4 °C. After washing, the
beads are treated with RNase (50 µg/ml) for 30 min at 37 °C and then
proteinase K overnight. The cross-links are then reversed by heating the
sample at 65 °C for 6 h. DNA is extracted by the phenol/chloroform method,
ethanol-precipitated, and resuspended in 100 µl of water. We performed a
total of six individual chromatin immunoprecipitations in the SW48 cell line
to obtain DNA enriched with methylated H3-Lys9 for cloning
purposes.
Cloning of H3-Lys9-enriched DNA FragmentsSW48
ChIP products were ethanol-precipitated and treated with mung bean nuclease to
make blunt ends, then cloned into the zero-blunt vector (Invitrogen). Colonies
having inserts were identified by EcoRI restriction enzyme digestion
and were sequenced at the MDACC core sequencing facility.
ChIP-PCRChIP products from SW48 and RKO were used for
confirmation PCR using the oligonucleotide primers as follows. Alu11-F,
CAGCCTGGGTGATAGAGCAAG; Alu11-R, AGAGAAAGAGGAAACACAAGGAGC; Alu21-F,
GCACCCAGCTGAATTTTCCA; Alu21-R, CTGGGTTTGGCTTTTGAATTG; Alu25-F,
ACCTCGTGATCCACCTGCC; Alu25-R, TTTTTTGAAGAACCTCCATACTGCT; Alu27-F,
TTTCATTTTGCTTTCTCACAGATTTT; Alu27-R, GGTCAACAGAGCAAGACTCCGT; Alu43-F,
CCCTCCAGTGAACCATCTCTG; Alu43-R, CAAGATCTGCCACTCCACTCC; P21-F,
GGTGTCTAGGTGCTCCAGGT; P21-R, GCACTCTCCAGGAGGACACA; MLH1-F,
CTTGCTTCTTTTGGGCGTCAT; and MLH1-R, GGCTTGTGTGCCTCTGCTGA; P16-F,
AGACAGCCGTTTTACACGCAG; P16-R, CACCGAGAAATCGAAATCACC; GAPDH-F,
TCGGTGCGTGCCCAGTTGAACC; GAPDH-R, ATGCGGCTGACTGTCGAACAGGAG.
The PCR products are visualized by agarose or 6% polyacrylamide gel
electrophoresis and quantitated by capillary electrophoresis using the Agilent
2100 bioanalyzer (Agilent Technologies). To ensure that PCR amplification was
in the linear range, each reaction was initially set up at different dilutions
of DNA for varying amplification cycle numbers, and we selected the final PCR
conditions accordingly. The assays were done in duplicate.
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RESULTS
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To identify genes linked to methylated histone H3-Lys9, we
performed ChIP using an anti-Lys9 methylated histone H3 antibody
and cloned the immunoprecipitated DNA (strategy described in
Fig. 1). Initially, we verified
that the library contained methylated H3-Lys9 enriched DNA
fragments by PCR using primers encompassing the promoter regions of P16,
hMLH1, P21, and GAPDH. P16 and hMLH1 are silenced, and
P21 and GAPDH are expressed in the SW48 cell line
(7). In our library, compared
with genomic DNA, the former two promoters showed a high degree of enrichment
and the latter two promoters showed specific depletion, in accordance with
known levels of H3-Lys9 methylation (data not shown). Having
verified the quality of the library, we then randomly selected 47 clones,
sequenced them, and characterized the sequences using BLAST
(www.ncbi.nlm.nih.gov/)
and BLAT
(genome.ucsc.edu/)
searches.
The results of sequencing are summarized in
Table I, and a representative
example is shown in Fig. 2.
Twenty-four (51%) of forty-seven clones contained Alu elements only.
Five clones had both Alu and long terminal repeats (LTR) or
Alu and long interspersed transposable element (LINE). Three
additional clones had Alu elements within 200300 bp of the
recovered fragment (clones 43, 44, and 45 had AluSg, -Ye,
and -Jb, respectively). Some of the sequences began or ended in the
middle of Alu elements, and the range of Alu element length
in the recovered clones was 95282 bp in each clone. Thus, overall, 32
of 47 (68%) clones were in or within 200 bp of an Alu element.
Considering that Alu elements form about 10% of the human genome
(16), this result indicates
marked enrichment for Alu elements in this library, suggesting a high
degree of H3-Lys9 methylation at this repetitive sequence.
Twenty-three (72%) of thirty-two Alu elements belonged to the old
Alu subfamily, and nine (28%) Alu elements were classified
into young Alu subfamilies. We also obtained 1 clone related to a
short interspersed transposable element (SINE) other than Alu. Three
clones contained LTRs only, and four clones contained LINE elements only,
respectively. Satellite region (ALR/Alpha) DNA was present in only 1 clone.
Including Alu elements, a total of 41 clones (87%) were related to
repetitive elements, which then form the bulk of DNA modified at
H3-Lys9. We found no CpG island within 3 kb of any clone.

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FIG. 2. Confirmation of H3-Lys9 methylation targets. A,
example of a recovered clone. Bold characters correspond to the
Alu sequence. The primer sites for ChIP-PCR are underlined.
B, examples of PCR confirmation of ChIP using antimethylated histone
H3-Lys9 antibody. In the assays, DNA combined with methylated
histone H3-Lys9 antibody is immunoprecipitated and detected by PCR
amplification. The promoters of P21 and MLH1 show a low and
high level of H3-Lys9 methylation in SW48 and RKO cell lines,
respectively. The intensity of the PCR bands was quantitated by densitometry
or using the Agilent 2100 bioanalyzer. C, ratios of precipitated DNA
over input DNA were calculated as a relative precipitated fold shown on the
y axis.
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To verify these results, we randomly selected 5 Alu clones and
prepared primer sets encompassing the Alu elements (ChIP-PCR). In
each case, at least one primer was located in the flanking region to ensure
that we were studying that specific Alu element
(Fig. 2A). ChIP-PCR
experiments using these primers in SW48 and RKO colorectal cancer cells are
shown in Fig. 2B.
MLH1 and P21 were used as controls. As we reported
previously (7), both SW48 and
RKO show high levels of H3-Lys9 methylation in the hMLH1
promoter and low levels of H3-Lys9 methylation in the P21
promoter, corresponding to gene suppression and activation, respectively. All
Alu elements showed a pattern similar to the hMLH1 promoter
in both cell lines. We summarized these quantitative analyses in
Fig. 2C. Ratios of
precipitated DNA over input DNA were high in all the Alu elements and
hMLH1 and low in P21, suggesting that Alu elements
are suppressed by H3-Lys9 methylation in a manner similar to
hMLH1 gene silencing in cancer. Primers that amplify many
Alu elements simultaneously (i.e. in the conserved
Alu sequence) showed similar results (data not shown).
Alu elements show high degrees of DNA methylation in human cells
(14,
17). Therefore, it is possible
that the H3-Lys9 methylation we observed was related to DNA
methylation and recruitment of a silencing complex. To test this hypothesis,
we examined the effects of inhibition of DNA methylation on Alu
H3-Lys9 methylation. To this end, we performed ChIP on SW48 cells
treated with the DNA methyltransferase inhibitor 5-aza-dC daily for 3
consecutive days. As shown in Fig.
3, all Alu elements and MLH1 showed a decreasing
level of H3-Lys9 methylation shortly after 5-aza-dC. These results
are consistent with our previous reports on non-repetitive, silenced genes and
suggest that H3-Lys9 methylation of Alu elements is
partially targeted by DNA methylation.

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FIG. 3. A, results of histone H3-Lys9 methylation ChIP assays in SW48
cells treated with 5-aza-dC (DAC). Assays were conducted as in
Fig. 2. B, ratios of
precipitated DNA over input DNA is shown on the y axis. Clone
identity is shown on the x axis. All Alu elements,
MLH1, and P21 show decreasing levels of H3-Lys9
methylation.
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DISCUSSION
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In this study we identified Alu elements as major targets for
histone H3-Lys9 methylation using chromatin immunoprecipitation.
Methylation at Lys9 on histone H3 has been shown to be a marker of
heterochromatin and to be associated with inactivation of gene expression
(5). In the promoter regions of
P16, hMLH1, and MGMT, we recently found increased H3-Lys9
methylation in cells with promoter DNA methylation-associated silencing
(7), and others have reported
similar findings (8,
9). Thus, H3-Lys9
methylation appears to be a ubiquitous marker of silencing in human cells and
likely leads to transcriptional repression by recruitment of a protein complex
such as the HP1-associated complex
(18).
The repetitive DNA at yeast centromeres is maintained in a
transcriptionally silent state by methylation of H3-Lys9 and
binding of Swi6 or heterochromatin protein 1 (HP1) to the modified chromatin
(19). A recent study of
centromere chromatin silencing in the fission yeast, Schizosaccharomyces
pombe, demonstrated that silencing of homologous repeats by
H3-Lys9 methylation is initially mediated by components of the RNA
interference machinery (20).
Intriguingly, gene silencing in inactivation of the X chromosome in mammalian
female cells involves the expression of Xist RNA, which coats the X
chromosome, followed soon after by H3-Lys9 methylation, gene
inactivation, and ultimately methylation of DNA
(21). The finding of
Alu elements as a target of H3-Lys9 methylation raises the
possibility that by analogy to yeast silencing of homologous repeats,
mechanisms involving RNA interference also operate in the establishment of
silenced Alu elements.
Among 32 Alu clones recovered here, the frequency of old
Alu elements (23 clones, 72%) and young Alu elements (9
clones, 28%) are consistent with the prevalence of old and young Alu
elements in the human genome. In older Alu subfamilies, many of the
CpG sites have mutated to TpG or CpA because of deamination of
5-methylcytosine. In contrast, newly retrotransposed Alu elements are
CpG-rich and extensively methylated. Our results show that histone
H3-Lys9 methylation is characteristic of both old and young
Alu subfamilies and suggests that, once established,
H3-Lys9 Alu methylation persists over long periods of
time, despite eventual inactivation of the Alu elements by promoter
mutations.
We also found another repetitive element, LINE, in 7 clones (15%). LINE-1
elements comprise roughly 15% of the human genome and are concentrated in
AT-rich regions (16). LINE-1
promoters are also usually methylated at DNA
(22), thus providing an
explanation for H3-Lys9 methylation. Nevertheless, the frequency of
LINE elements in our clones was almost similar to that in the human genome,
suggesting that LINE elements are less specifically targeted than Alu
elements, although the number of clones analyzed overall in this study is
small.
It remains unclear which protein complexes are involved in Alu
silencing when these sequences are highly methylated. The SNF2h-NuRD-cohesin
complex, which is a chromatin remodeling complex, was recently reported to
specifically associate with some Alu elements, accompanied by histone
H3-Lys4 methylation and either histone H3 or H4 acetylation
(23). In that study, the
binding of the cohesin complex to chromatin around Alu elements could
be increased by inhibition of DNA methylation. In our study, treating cells
with 5-aza-dC decreased the degree of H3-Lys9 methylation in all 5
Alu elements tested. It is possible then that the SNF2h-NuRD-cohesin
complex counteracts the activity of a silencing complex recruited by histone
H3-Lys9 methylation and that normally reside on Alu
elements, possibly as a result of DNA methylation in these regions.
An obvious functional significance of these findings is to provide a
molecular mechanism for the known silencing of Alu elements. This
silencing is thought to be essential in reducing the mutational load
associated with active Alu elements in dividing cells, as has been
proposed in the genome defense hypothesis
(24). It is of interest,
however, that H3-Lys9 methylation can spread in cis, as
seen in fission yeast (25). If
similar spreading occurs in human cells, one might observe time-dependent
spreading of silencing, a hypothesis consistent with the observations of
age-related DNA methylation in normal tissues
(26,
27). Furthermore, such
Alu element H3-Lys9 methylation may serve as an initial
seed for gene silencing in cancer, as suggested by previous studies
(2830).
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FOOTNOTES
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* This work was supported in part by National Institutes of Health Grant
R33CA89837 and by the George and Barbara Bush fund for innovative cancer
research. DNA sequencing in the M. D. Anderson Cancer Center core sequencing
facility is supported by Core Grant CA16672 from the National Institutes of
Health. The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section 1734
solely to indicate this fact. 
Supported by the Uehara Memorial Foundation in Japan. 
To whom correspondence should be addressed: Dept. of Leukemia, M. D. Anderson
Cancer Center, Unit 428, 1515 Holcombe Blvd., Houston, TX 77030. Tel.:
713-745-2260; Fax: 713-794-4297; E-mail:
jpissa{at}mdanderson.org.
1 The abbreviations used are: ChIP, chromatin immunoprecipitation; LTR, long
terminal repeats, SINE, short interspersed nuclear elements; LINE, long
interspersed nuclear elements; 5-aza-dC, 5-aza-2'-deoxycytidine; GAPDH,
glyceraldehyde-3-phosphate dehydrogenase. 
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