Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma
Hervouet et al. Clinical Epigenetics
Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma
Eric Hervouet 0 1
Paul Peixoto 0 1
Régis Delage-Mourroux 1
Michaël Boyer-Guittaut 1
0 EPIGENExp (EPIgenetics and GENe EXPression Technical Platform) , Besançon , France
1 INSERM unit 1098, University of Bourgogne Franche-Comté , Besançon , France
Our current view of DNA methylation processes is strongly moving: First, even if it was generally admitted that DNMT3A and DNMT3B are associated with de novo methylation and DNMT1 is associated with inheritance DNA methylation, these distinctions are now not so clear. Secondly, since one decade, many partners of DNMTs have been involved in both the regulation of DNA methylation activity and DNMT recruitment on DNA. The high diversity of interactions and the combination of these interactions let us to subclass the different DNMT-including complexes. For example, the DNMT3L/DNMT3A complex is mainly related to de novo DNA methylation in embryonic states, whereas the DNMT1/PCNA/UHRF1 complex is required for maintaining global DNA methylation following DNA replication. On the opposite to these unspecific DNA methylation machineries (no preferential DNA sequence), some recently identified DNMT-including complexes are recruited on specific DNA sequences. The coexistence of both types of DNA methylation (un/specific) suggests a close cooperation and an orchestration between these systems to maintain genome and epigenome integrities. Deregulation of these systems can lead to pathologic disorders.
DNA methylation; DNMT1; DNMT3A; DNMT3B; DNMT3L; Epigenetics; DNMT-including complexes
DNA methyl transferases are the catalytic players of DNA
DNA methylation, occurring in CpGs motifs, is the
reaction catalyzing the covalent transfer of a methyl
group from S-andenosyl methionine (SAM) to the fifth
carbon of cytosines (C). DNA methylation is involved
in numerous biological events (e.g., embryonic
development, parental imprinting genes, transposon silencing,
X inactivation, cancer), and it concerns about 70–80%
of CpGs in mammalian DNA. DNA methylation, which
is generally observed in a condensed chromatin and
associates with transcriptional gene silencing when it
occurs in promoters, is processed by two distinct
mechanisms: (i) the inheritance DNA methylation that
allows the maintenance of DNA methylation marks on
the new strand using the parental methylated strand as
a matrix, following DNA replication and (ii) de novo
DNA methylation which occurs on both strands
independently of DNA replication. De novo methylation
happens predominantly during embryogenesis and is
further maintained by the DNA methylation inheritance
machinery after DNA replication and cell division.
DNA methylation is processed by a family of enzymes,
the DNA methyl transferases (DNMTs), which are
divided in three classes: DNMT1, DNMT2, and the
DNMT3A/3B/3L. The DNMT2 functions have been
poorly investigated: This enzyme may methylate the
consensus sequence TTNCGGAR but DNMT2 is
probably mainly involved in the methylation of C38 of
]. Our review will focus on DNMT1,
DNMT3A, DNMT3B, and DNMT3L.
DNMT1, the major enzyme involved in DNA methylation
DNMT1, a large protein of 1616 amino acids (aa) which
mainly catalyzes DNA methylation inheritance activity,
is composed of a large regulator N-terminal region
(1000 aa) and a small catalytic C-terminal region. In
this last region, 10 catalytic domains are essential for
the interaction with the SAM. C-ter and N-ter regions
are linked by 12 repeats of KG di-peptides. The N-ter
region is composed of (i) a binding protein domain able
to interact with a large panel of proteins [
], (ii) a RFTS
(replication focus targeting sequence) domain involved
in the recruitment of DNMT1 into the DNA replication
fork, (iii) a zinc-binding domain, (iv) some BAH
domains (adjacent homology domain), and (v) a nuclear
localization signal (NLS) (aa 191–211) (Fig. 1).
However, the role of the N-ter region in DNMT1 activity
remains unclear. Some authors showed that DNMT1
activity was independent from this region [
reported that the interaction of the N-ter region with
the C-ter region, which is promoted by the S515
phosphorylation, was required for tri-dimensional (3D)
modification of DNMT1 and its activity. Furthermore,
DNMT1 also presents an allosteric site (aa 284–287:
independent from the catalytic site) which may bind 5mC
and increase fit for both SAM and DNA [
DNMT3A and DNMT3B, the enzymes predominantly
associated with de novo DNA methylation
De novo DNA methylation activity, catalyzed by
DNMT3A and DNMT3B, is essential during
embryonic development or gametogenesis but is also
frequently associated to aberrant gene repression in
many pathologies (e.g., cancer) [
]. The structures of
DNMT3A and DNMT3B are very close and are
composed of (i) a N-terminal region comprising a PWWP
domain which is essential for DNA binding, (ii) a
PHD-like ADD domain involved in protein/protein
interactions, and (iii) a C-terminal region responsible
for the catalytic activity (Fig. 1). A small preference
for the recruitment on unmethylated DNA was seen
for DNMT3A whereas DNMT3B might link both
hemi and unmethylated DNA. Finally, a third but
catalytically inactive member of the DNMT3 family,
DNMT3L, which is mainly expressed during
development, is required for gene imprinting and the
regulation of DNMT3A/B.
Since 10 years, our knowledge on the roles of DNMTs
in DNA methylation has highly raised. More and more
partners of each DNMT have been reported, and our
view of DNA methylation machineries is currently
moving, let us understand that (i) crosstalks exist
between de novo and maintaining DNA methylation
machineries and (ii) DNA methylation can be mediated by
different DNMT-including complexes and some of
them are not associated with specific DNA sequences
while other complexes may target the methylation in a
specific loci. The different kinds of DNMT-including
complexes involved in DNA methylation are
summarized in Fig. 2 and will be discussed below.
PCNA and UHRF1 Mutations in the RFTS domain of
DNMT1 dramatically reduced its activity. Moreover, this
RFTS domain is probably involved in the allosteric
activation of DNMT1. Indeed, stable DNMT1 homodimers are
linked by a hydrophobic interaction requiring the RFTS
domain of each DNMT1. Although monomeric DNMT1
presented a 2- to 50-fold increase activity in the presence of
hemi-methylated DNA, compared to methylated DNA,
many different partners could also be involved in the
recruitment of DNMT1 on hemi-methylated DNA [
strong association between DNMT1 and the replication
machinery may explain the large concomitance of DNA
replication and maintaining of DNA methylation .
Numerous reports showed that DNMT1/PCNA (proliferative
cell nuclear antigen) interaction was essential for DNMT1
]. PCNA which bound to the new
replicated DNA strand is assumed to take down from the DNA
polymerase and consequently favor DNMT1 recruitment.
Indeed, the DNMT1/PCNA interaction could also modify
the structure of the RFTS DNMT1 domain and by a
ricochet increase in both DNMT1 affinity for DNA and its
]. Opposite studies showed that the disruption of
the PCNA binding domain of DNMT1 (aa 51–255), only
reduced from twofold the DNA methylation maintaining
activity, suggesting that PCNA was not essential. Bostick et al.
and Sharif et al. have reported that UHRF1/DNMT1
interaction (UHRF1, ubiquitin-like PHD and RING finger
domain 1; also called ICBP90 (inverted CCAAT box binding
protein of 90 kDa) in human or Np95 in mouse) was also
involved in DNMT1 recruitment [
]. UHRF1 was first
described for its E3 ubiquitin ligase activity on histone H3.
UHRF1 also promotes DNA methylation inheritance
preferentially during mid to late S phase where it accumulates in
nuclear loci and favors the targeting of DNMT1 on
hemimethylated DNA. The DNMT1/UHRF1 interaction involves
the SRA (SET and RING) domain of UHRF1 which also
recognizes hemi-methylated CpG and three independent
regions of DNMT1 (aa 1–446; 401–615; 1081–1408) [
Crystal resolution of the SRA domain of UHRF1 and
mutagenesis experiments revealed that R443, Y466, and D469
residues were essential for DNA binding [
Invalidation of PCNA/DNMT1/UHRF1 complex using competitor
peptides of DNMT1/PCNA and DNMT1/UHFR1
interactions, or knock down of DNMT1, strongly decreased the
global DNA methylation and induced severe defects such
as mitotic catastrophe [
HDAC1 and G9a The concomitant presence of several
repressive marks has often been observed on silenced
promoters. Indeed, the presence of 5mC is often correlated
with histone deacetylation, suggesting that DNA
methylation and histone regulation machineries thinly cooperate.
Maintaining of DNA methylation in heterochromatin
required DNMT1/HDAC1 interaction and the deacetylation
of histones [
]. HDAC2 and the histone methyl transferase
(HMT) G9a (which catalyzes the repressive marks mono-,
di-, and less efficiently trimethylation of H3K9 and H3K27)
could also be recruited in the DNMT1/UHRF1/HDAC1/
HDAC2/G9a complex via direct DNMT1/G9a, UHRF1/
G9a, and UHRF1/HDAC2 interactions. The role of G9a is
still in debate, as on the one hand, its inhibition caused a
DNA hypomethylation in some imprinting genes, but on
the other hand, G9a was dispensable for maintaining DNA
methylation in somatic cells [
]. UHRF1 recruitment
on repressed promoters is reinforced by the affinity of its
tandem tudor domain with the N-ter tail of H3K9me2/3,
independently of the DNA methylation status .
Nevertheless, overexpression of both UHRF1 mutants incapable
of binding hemi-methylated DNA or incapable of binding
H3K9me3 partially restored global DNA methylation [
In conclusion, the DNMT1/PCNA/UHRF1/HDAC/G9a
complex is preferentially recruited on chromatin in S phase
where it promotes DNA methylation, histone deacetylation,
and H3K9/H3K27 methylation [
Maintaining DNA methylation activity in other
Although most of the unspecific inheritance DNA
methylation activity is probably processed by the DNMT1/PCNA/
UHRF1/HDAC/G9a complex, additional DNMT1-including
complexes have been reported.
Cooperation of DNMT1 with nucleosome-related
proteins and HMTs (HP1, SUV39H1, SNF2H) Following
DNA replication, some nucleosomes are deposited on the
new replicated strand. Kinetics of histone modifications and
DNA methylation are highly related but are dependent of
both, the local DNA sequence and the nature of DNMTs/
HDACs/HMTs complexes recruited. Although, in vitro, the
DNA methylation of heterochromatin can be catalyzed by
free DNMT1 on mononucleosomes, the interaction of
DNMT1 with the ATP-dependent nucleosome remodeler
SNF2H (SNF2 homolog) strongly increased DNMT1
recruitment on these nucleosomes [
]. Some HMTs are
predominantly associated with euchromatin such as G9a
(found in the DNMT1/PCNA/UHRF1/HDAC/G9a, see
above) while others such as SUV39H1 (suppressor of
variegation 3–9 homolog 1; catalyzes H3K9me3) are recruited
on heterochromatin. Both kinds of HMTs could also
regulate the DNMT1 recruitment in a direct or indirect
DNMT1/HMT interaction manner. Indeed, the recognition
of H3K9me by HP1 (heterochromatin protein-1) may serve
for a further recruitment of DNMT1/SUV39H1/HP1
]. A similar mechanism has also been
observed for the euchromatin G9a-mediated H3K9me2
methylation which could also be recognized by HP1.
Indeed, G9a/HP1 interaction induced both an increase in
G9a activity and DNMT1 recruitment . Conversely,
DNMT1 was required for H3 deacetylation and di- and
trimethylation of H3K9 in cancer cells [
]. Similarly, DNA
methylation and histone methylation need both DNMT1
and SUV39H in zebrafish [
]. However, in some cases,
the HMT/DNMT1 interaction could be independent from
DNA methylation: For example, the DNMT1 mutant,
depleted for its catalytic domain, was still able to control the
H3K4 demethylase LSD1 (lysine-specific demethylase 1A,
also called KDM1) recruitment and to induce gene
repression without DNA methylation (e.g., MAGEA10) .
DNMT1/CFP1 CFP1 (CysxxCys finger protein 1), which
presents a high affinity for unmethylated DNA, has been
shown to interact with DNMT1 (via aa 169–493, TS and
]. CFP1−/− ES cells, showed a reduction of
70% of DNA methylation in single copy genes while a
specific inhibition of DNMT1/CFP1 interaction strongly
decreased tumor growth of glioma cells in nude mice [
DNMT1/MBDs MBDs (methyl-CpG-binding domain
protein) are organized in a family of five proteins
(MeCP2, MBD1–4) known to interact with methylated
DNA and are also involved in the recruitment of
DNMT1. Indeed, the MBD2/MBD3 heterodimer which
preferentially interact with hemi-methylated DNA could
also recruit DNMT1, during late S phase, in replication
]. MeCP2 was also known to form a ternary
repressor complex with HDAC1 and mSIN3A (SIN3
transcription regulator family member A), a protein
involved in the regulation of histone acetylation.
Competition between DNMT1 and mSIN3A, for an interaction
with the TRD (transcription repression domain) of
MeCP2, disrupted the MeCP2/HDAC1/mSIN3A
complex in benefits of the recruitment of DNMT1 on
hemimethylated DNA and favored DNA methylation [
DNMT1/DMAP1 DMAP1 (DNMT-associated protein1)
is a transcriptional co-repressor also involved in DNA
methylation inheritance. DNMT1/DMAP1 interaction
(via aa 12–105 of DNMT1) was involved in both early
(euchromatin) and late S phase (heterochromatin) of
DNA replication and in the recruitment of PCNA [
The DNMT1/DMAP1 complex has been shown to
repress glucocorticoid receptor target genes. This silencing
also required the DMAP1-mediated recruitment of the
multifunctional protein DAXX (death domain-associated
protein) whose roles have been previously reported in
apoptosis and transcriptional repression [
HDAC2 could also associate with the DNMT1/DAMP1
complex in late S phase and promote gene silencing
]. On the opposite, RGS6 (regulator of G protein
signaling 6) could compete with DNMT1 for the
interaction with DMAP1 and disrupt DNMT1/DMAP1
In spite of the absence of a clear affinity for a particular
DNA sequence, each DNMT1-including complex could be
associated to a different or a partially redundant DNA
methylation profile. Indeed, a specific peptide-mediated
disruption of DNMT1/PCNA, DNMT1/HDAC1, DNMT1/
DNMT3B, or DNMT1/HP1 interactions promoted global
DNA hypomethylation in astrocytes and increased tumor
27, 56, 57
]. On the opposite, a specific inhibition of
DNMT1/DMAP1 interaction increased the temolozomide
response in glioma cells, suggesting that inhibition of
specific DNMT-including complexes could be used in the
future in combination with classical chemotherapeutic agents.
Maintaining DNA methylation activity and pathologies
DNMT1 and viral oncoproteins As already seen above,
DNA methylation deregulation is associated with
tumorigenesis. An association of DNMT1 with two distinct viral
oncoproteins has been reported. Both DNMT1/E1A (in
adenovirus) and DNMT1/E7 (in papillomavirus) interactions
increased inheritance DNA methylation. Although
mechanisms governing this phenomenon are still unclear, it has
been proposed that viral oncoproteins might, as already
described for DNMT3L, promote DNMT1 DNA binding and
SAM recruitment [
Regulation of inheritance DNA methylation activity
A deregulation of inheritance methylation activity was
reported in many pathologies. Indeed, in lupus patients,
a decrease of DNMT1 was mediated by the
overexpression of miRNA-21 (microRNA) and miRNA-148a that
control the DNMT1 gene expression [
]. In acute
myeloid leukemia cells, miRNA-29b inhibited the expression
of SP1 (specific protein-1, TF required for DNMT1
expression) and consequently decreased DNMT1
]. In spite of global DNA hypomethylation and a
decrease in maintaining methylation activity, a decrease
of DNMT1 content was rarely observed in solid tumors.
Numerous post-translational modifications of DNMT1
could modulate its activity in cancers. Indeed, Casein
kinase-1 induced the S146 phosphorylation of DNMT1
and decreased the DNA binding capacity of this enzyme
]. S127 and S143 phosphorylations mediated by PKC
(protein kinase C) and AKT (also called PKB, protein
kinase B) were observed in glioma and provoked the
disruption of DNMT1/PCNA/UHRF1 complex and a
consecutive global DNA hypomethylation [
]. On the
opposite, S143 phosphorylation could also block the
SET-7-mediated K142 methylation which normally
promotes proteasomal degradation of DNMT1 [
increase in the stability of DNMT1 was also reported
following its demethylation by LSD1 [
]. Moreover, 10
putative sites of sumoylation were reported in DNMT1
whose roles are still unclear [
Role of DNMT3A/3B in DNA methylation inheritance
In spite of their predominant role in de novo methylation,
DNMT3A and DNMT3B are also involved in maintaining
DNA methylation [
]. Cooperation between DNMT1 and
DNMT3A, due to a partially redundant and/or a
complementary maintaining activity, has been reported in
postmitotic neurons [
]. Direct interaction between N-ter
regions of DNMT1 and of DNMT3A/B has been involved
in this cooperation [
]. Indeed, these interactions were
necessary for maintaining DNA methylation of
heterochromatin in embryonic cells. Indeed, DNMT3A and/or
DNMT3B invalidation(s) induced a loss of maintaining of
DNA methylation in specific loci (e.g., hypomethylation of
imprinted genes IGF2 and XIST) and a progressive global
DNA hypomethylation [
]. Jeong et al. proposed a
model, in which a pool of DNMT3A and DNMT3B already
bound to nucleosomes in CG-rich regions could catalyzed
the inheritance methylation of CpGs previously missed by
DNMT1 during the reading of hemi-methylated DNA
following DNA replication .
In cells, maintaining and de novo DNA methylation
activities are not compartmentalized and evident crosstalks
between these machineries have been underlined. Indeed, in
colorectal cancer cells, invalidation of DNMT1 or DNMT3B
had minor effects on global DNA methylation while double
invalidation reduced to more than 90% the 5mC content
]. Moreover, a close cooperation between DNMT1
and DNMT3s was reported for the methylation of specific
genes in cancer cells. For example, we reported that
DNMT1 and DNMT3A were necessary for the methylation
of the CASP8 promoter in glioma cells [
Unspecific de novo DNA methylation machineries
De novo DNA methylation activity is mainly catalyzed by
DNMT3A and DNMT3B
Mutations in the DNMT3B gene induce a specific
hypomethylation of heterochromatin satellite-2 sequences leading to
the ICF (immunodeficiency, centromeric instability, and
facial dysmorphism) syndrome. Indeed, de novo DNA
methylation of CpG-rich sequences (e.g., satellite-2
sequences) could be easily catalyzed by a processive enzyme
such as DNMT3B (DNMT3B presents six additional
positives charges in C-ter), whereas DNMT3A is a distributive
]. Contrary to DNMT1 which is mainly recruited
in replication loci during S phase, DNMT3A and DNMT3B
are not focused to these loci. For example, during DNA
replication, DNMT3B can interact with hCAP-C, E, and G
(human chromosome-associated protein) and three
members of the condensin complex responsible for chromosomal
condensation. This suggests that DNA methylation
catalyzed by DNMT3B is, at least, partially independent from
DNA replication [
]. Moreover, an increase of de novo
DNA methylation activity of DNMT3B following its
interaction with NEDDylated CUL4A (CUL4A-NEDD8) could
be involved in local DNA hypermethylation and was
reported in tissues (e.g., breast cancer (BC) and hepatoma)
overexpressing CUL4A .
DNMT3A/DNMT3B/DNMT3L and heterochromatin
The absence of methylation of H3K4 (H3K4me0) also
controls the DNMT3 recruitment on chromatin during
gametogenesis and embryogenesis. Moreover, the identification
of H3K4me0 by DNMT3L (via PHD domain) could also
promote in a DNMT3L/DNMT3A/3B interactions manner,
the recruitment of DNMT3A and DNMT3B on DNA.
Crystal structure of DNMT3L/DNMT3A complexes
revealed that these proteins associated in dimers or tetramers
(1–2 DNMT3A linked via their C-ter region to the C-ter
region of 1–2 DNMT3L) [
]. These complexes
induced a refolding of DNMT3A that increased its DNA
binding capacities and de novo methylation activity of 2- to
]. The recruitment of DNMT3A/
DNMT3L-including complexes was more frequent in Alu
sequences, in the promoters of imprinted genes and in
CpG-rich regions with CpG spaced from 8 to 10 pb [
]. About 100 imprinted genes were described in
mammals, and most of them are grouped in clusters. Although
both DNMT3A and DNMT3B have been involved in the
nuclear localization of DNMT3L, the DNMT3A/DNMT3L
interaction seems the most important for gene imprinting,
since invalidation of DNMT3A or DNMT3L alone
provoked a loss of imprinting marks and gene reactivation but
not the DNMT3B KO [
DNMT3A/B-including complexes and histones marks
As seen above for unspecific maintaining DNA
methylation, de novo methylation also frequently requires
cooperation between DNMTs and chromatin remodelers
]. e.g., interaction of DNMT3A and DNMT3B with
LSH (lymphoïd-specific helicase), a member of the
SNF2-related family, increased the processivity of these
DNMTs and their DNA binding capacities [
invalidation, in ES cells, provoked a hypomethylation of
DNA repeat elements and expression of specific genes
]. Recruitment of HDACs in the fleeting
could also increase the repressor activity of LSH .
Indeed, during oogenesis, the repression of imprinted
genes was achieved by histone modifications and the
co-recruitment of HDAC1 mediated by the PHD
domain of DNMT3L. HDAC1 and/or HDAC2 may be also
recruited by a direct interaction with DNMT3A and
Fig. 3 Examples of cooperation between DNA methylation machineries and proteins regulating post-translational modifications of histones. Left: Silencing of
a DNA region following DNA replication. Addition of the repressive H3K9me3 mark, removal of H3 acetylation (Ac) and methylation of the new DNA strand is
catalyzed by the DNMT1/UHRF1/PCNA/G9a/HDAC1 complex. Right: de novo methylation of a DNA region of heterochromatin (e.g., major satellites). The
addition of the H3K9me3 repressive mark by SUV39H1 is read by HP1 and that further induces the recruitment of DNMT3A and/or DNMT3B for de novo
methylation of both strands of DNA. Black circles: 5mC; white circles: C. Parental strand: blue; new synthetized strand: orange
DNMT3A could also directly read the H3K36me3 and
H4R3me2 marks to complete gene repression in a DNA
methylation manner (e.g., B-GLOBIN gene), suggesting
that de novo methylation activity is also closely related to
histone methylation [
]. Moreover, de novo DNA
methylation occurring in heterochromatin could be
initiated by the SUV39H1-mediated H3K9me3 methylation
which could be recognized by HP1. HP1 can finally recruit
DNMT3A and/or DNMT3B for DNA methylation (Fig. 3)
. SUV39H1/DNMT3B interaction was mainly
involved in pericentric heterochromatin methylation and
not in centromeric methylation, suggesting that different
mechanisms are required in regard of heterochromatin
localization. On the opposite, the anchorage of DNMT3B
on centromeric areas was favored by its interaction with
the centromeric protein CENP-C (via the PWWP domain
of DNMT3B) [
Similar mechanisms were also reported in euchromatin:
as an example, the kinetic of TNFα gene silencing required
(i) an initial addition of the H3K9me2/3 mark by G9a, (ii)
the identification of this mark by HP1, and (iii) the silencing
was then completed by the recruitment of DNMT3A and
DNMT3B for DNA methylation [
93, 94, 106
SETDB1 (SET domain bifucarted 1; also called ESET),
another HMT, specific of euchromatin, could also directly
interact with DNMT3A and DNMT3B, but not with
DNMT1 (even if SETDB1 could be indirectly associated
with DNMT1 via SETB1/MBD1 interaction), to induce
gene silencing [
], e.g., the repression of the RASSAF1A
gene required (i) addition of H3K9me3 marks on the
promoter by the SETDB1/HDAC1 complex, (ii) recruitment of
DNMT3A (via DNMT3A/SETBD1 and DNMT3A/HDA
C1 interactions), and (iii) DNA methylation. The formation
of the BRG1/G9a/DNMT3A complex was induced
following stress induction in mice and responsible for
the repression of the motor MYH6 gene and cardiac
The direct methylation of the murine DNMT3A
(K44me2) by G9a or by GLP (G9a-like protein) could also
be recognized by MMP8 (M-phase phosphoprotein 8). The
DNMT3A/MPP8/G9a(or GLP) silencing complex was
predominantly recruited close to H3K9me marks [
DNMT3A/DNMT3B/UHRF1 UHRF1, the essential
component of the unspecific maintaining DNA
methylation activity catalyzed by the DNMT1/PCNA/UHRF1/
G9a complex, is also able to interact with DNMT3A and
DNMT3B independently of the presence of DNMT1
]. These interactions require the N-ter regions of
DNMT3A and DNMT3B and the SRA domain of
UHRF1 (also included in DNMT1/UHRF1 interaction).
Indeed, in ES transfected cells, silencing of the
exogenous CMV promoter was dependent of the presence of
UHRF1, G9a, SUV39H, DNMT3A, and DNMT3B.
De novo DNA methylation is partially catalyzed by DNMT1
Although DNMT1 is predominantly involved in
maintaining DNA methylation and that its affinity for
hemimethylated DNA is 2- to 50-fold more important than for
unmethylated DNA, large high-resolution sequencing of
repetitive elements or of single copy genes revealed a role of
DNMT1 in de novo methylation [
]. Indeed, de novo
methylation of genes frequently observed in cancers could
be catalyzed by DNMT1 rather than DNMT3A or
]. Moreover, de novo methylation of
the D4Z4 subtelomeric repeat was dependent of DNMT1
and not DNMT3B . Among the three areas of
DNMT1 mapped to interact with DNA, the Zn-binding
domain which recognizes methylated DNA, has been
involved in de novo methylation activity of DNMT1 [
Recruitment of DNMT1 (via the allosteric site in the N-ter)
to already methylated DNA, also increases its de novo
methylation activity. Similarly, de novo DNA methylation,
catalyzed by DNMT3A, promoted a consecutive increase
in de novo methylation activity of DNMT1. Interaction of
USP7 with DNMT1 (via USP7 C-ter domain of USP7 and
DNMT1 TS domain) and UHRF1 (via USP7
TRAFdomain and UHRF1 SRA-domain) also stimulated both
inheritance and de novo methylation activities of DNMT1
and stabilized UHRF1 content via its deubiquitination
]. All of these observations strongly suggest a tight
cooperation between all DNMTs in de novo methylation
activity, even if putative partners involved in these
processes, are largely unknown.
Specific recruitment of DNA methylation machineries
As seen above, de novo methylation is crucially related to
many pathologies. In cancer cells, a paradoxal global DNA
hypomethylation is frequently concomitant with both local
hypo and hypermethylations of genes. These defects in
DNA methylation could induce TSG silencing or resistance
to cells death inducers [
]. In glioma cells, DNA
demethylation of promoters, following specific inhibition of
DNMT1, DNMT3A, or DNMT3B, was not fully redundant
suggesting the existence of different target patterns for
these enzymes [
]. Indeed, the direct interaction of
DNMT1 (via its TS domain) or of DNMT3A and
DNMT3B (via their PWWP domain) with DNA are not
very specific and only an inaccurate consensus could be
measured for preferential DNMTs targeting. Favorable
sequence for DNMT1-mediated methylation was associated
with an absence of G in − 1 position, while DNMT3A
preferentially methylated sequences with pyrimidines in − 2
and + 1 positions [
]. We predicted that DNMT1,
DNMT3A, and DNMT3B respectively preferentially
T/C), (T/A/C)(A/T)(T/G/A)CG(T/G/C)G(G/C/A), and (A/
C)(C/G/A)(A/G)CGT(C/G)(A/G). Others reported that
CANAGCTG and CCGG(A/T)NC(C/G)C sequences were
more frequently found in methylated genes, following
overexpression of DNMT3A and DNMT3, respectively [
However, recurrent profiles of de novo methylation were
observed in cancers, suggesting that DNMTs could be
specifically targeted on particular loci. The idea that “targetors”
able to target DNA methylation machineries on appropriate
sites has emerged since 10 years. The precise mechanisms
explaining how specific de novo methylation occurs are still
poorly understood. However, the discovery of particular
DNMT-including complexes able to be recruited on
specific loci and the fact that a single CG methylation among
300 pb in a promoter was enough to drop gene expression
argues that specific de novo methylation could be mainly
regulated via DNMT-“targetors” interactions (Fig. 4).
DNA repair requires specific DNA methylation
The mechanisms involved in DNA repair, following
DNA breakages, abasic sites formation or inappropriate
matching, have been intensively investigated. However,
the question of how epigenetic marks are repaired is still
unclear. Indeed, 5mC are mutational hotspots, as the
non-correction of a 5mC deamination lead to the
incorporation of T:G mismatches in DNA. Even if 5mC
deamination is properly corrected by a C, loss of
methylation can potentially upregulate the expression of
the concerned genes. The association of DNMTs with
DNA repair machineries may also occasionally provoke
de novo methylation and aberrant gene silencing.
Indeed, DNMT1 could interact with the MMR (mismatch
repair), the major DNA repair complex. DNMT1
recruitment on DNA break was independent of DNA
replication and S phase, but was still mediated by PCNA
]. Moreover, the recruitment of PCNA on DSB
(double-strand break) DNA also required both PCNA/
DMAP1 and PCNA/MUTS interactions (MUTS is a
member of MMR and presents a strong affinity for
hemi-methylated DNA) [
]. Cell irradiation also
provoked an accumulation of DNMT1 but not of DNMT3A
DNMT3A or DNMT3B was also involved in DNA
methylation following DNA repair, via a direct
association with MBD4 (methyl-CpG-binding domain
protein 4) and TDG (G/T mismatch-specific thymidine
DNA glycosylase), two enzymes involved in the (base
excision repair) BER complex [
]. SIRT1 can also
favor the recruitment of DNMT3B and members of
the polycomb group (PcG) complex on DSB DNA
]. These interactions involved both the
PWWP and catalytic domains of DNMT3A and
newly replicated strand
DNMT3B and increased TDG activity while TDG
concomitantly regulated DNMT3 activity. Once the DNA
base is repaired, BER proteins detached from DNA
and DNMT3s might methylate the new incorporated
cytosine. Finally, DNMT1 and the TDG/DNMT3A/
DNMT3B complex could also cooperate during active
demethylation, independent of the presence of DNA
damage. For example, a dynamic
methylation/demethylation process, involving this complex, was reported
on the PS2 promoter [
Specific DNMT recruitment mediated by transcriptional
activators or repressors
In many cancers, the activation of the oncogene Ras
induces a variety of events in favor of tumorigenesis, and
among them, the specific silencing of a particular panel of
genes. For example, the repression of the proapoptotic gene
Fas was specifically mediated by a coordination of different
complexes including 28 RESEs (Ras epigenetic effectors)
leading to the recruitment of DNMT1 and the methylation
of FAS promoter [
Recruitment of DNA methylation machineries by polycomb
The polycomb group (PcG) system is composed of four
interdependent multi-protein repressor complexes (PRC1
and 2/3/4) involved in the regulation of homeotic genes
during development and chromatin remodeling in stem cells.
Since some particular areas of DNA are controlled by PcG
and are generally highly methylated, it has been suggested
that PcG complexes are connected to DNA methylation
machineries, to silence specific loci. PRC1–4 multi-protein
complexes sequentially inhibit HOX genes expression by (i)
inducing PRC2-mediated ubiquitinylation of H2AK119, (ii)
inducing the PRC1-mediated H3K27me3 mark, (iii) a direct
interaction of BMI1 (which catalyzes the ubiquitin ligase
activity of PRC1) with DMAP1 leading to the recruitment of
DNMT1 and the silencing of particular genes [
similar complex composed of DNMT1, NSPc1 (nervous
system polycomb), a homolog of BMI1, and EZH2 (enhancer
of zest homolog 2; H3K27 methyltransferase, member of
PRC2) also specifically silenced HOX genes [
hypermethylation observed in colon cancer could be
partially regulated by PcG/DNMTs interactions. Indeed, 47% of
genes regulated by DNMT3B in these tumors also bound
PRC1 or PRC2 [
]. In ES cells, the specific de novo
methylation of the MYT1 promoter was dependent of
interactions between DNMT3A or DNMT3B (via their PHD
domain) and PRC components, and the recruitment of the
complex on the MYT promoter was performed in an
EZH2-dependent manner. Interestingly, in these cells, the
EZH2-dependent recruitment of DNMT3A was associated
with H3K27me3 but not always with DNA methylation
suggesting new roles for DNMT3A on gene repression
independently of de novo methylation [
The presence of transcriptional repressors in
DNMTincluding complexes may explain some specific targeting of
DNMTs. Indeed, the complete silencing of the OCT-4 gene
which occurs during development required (i) the local
G9a-mediated H3K9 methylation and (ii) the recruitment
of MBD2, MBD3, and GCNF/DNMT3A/DNMT3B
complex on specific RAREs boxes specifically recognized by the
repressor GCNF (germ cell nuclear factor) [
Moreover, the helicase WRNp (Werner protein) which
accumulated in OCT-4 promoter and interacted with G9a
also favored a direct interaction of G9a with DNMT3A and
DNMT3B (via ANK domain of G9a) [
Interaction of DNMT3A with the transcriptional repressor
RP58 also promoted the recruitment of DNMT3A on RP58
response elements although local DNA methylation was not
]. Additional repressor/DNMTs interactions
could also explain the specific gene silencing frequently
observed in numerous pathologies: Indeed, the HBX
(hepatitis B virus x protein) mediated specific repression of genes
(e.g., IL-4 or IGFBP-3) and required direct interactions of
HBX with both DNMT3A and HDAC1 [
The specific silencing of gene coding for rRNA (rDNA)
requires both DNA methylation and chromatin remodeling
and is orchestrated by a putative complex including TIP5
(TTF-I interacting protein 5), SNF2h, HDCA1, DNMT1,
and DNMT3B. Interaction of TIP-5 with H4K16ac marks
on rDNA was required for the recruitment of HDAC1,
DNMT1, and SNF2h and for the consecutive local
deacetylation and DNA methylation in these promoters [
When transcriptional factors are required for epigenetic
Specific recruitment of DNMT1 by TFs
Roles of TFs in DNA methylation are still unclear.
However, in regard to recent data of literature, it appeared
that DNMTs are able to “use” a TF as a co-repressor.
DNMT1 activity is processive, but we reported that
methylation of several CpGs within the same promoter
could be catalyzed by different DNMT1-including
complexes. Indeed, maintaining of DNA methylation of some
CpGs in the SLIT2 promoter was mainly processed by the
canonical DNMT1/PCNA/UHRF1 complex, but
methylation of specific CpGs localized in or near a SP1 box, within
the promoter, was methylated by the DNMT1/SP1 complex
(Fig. 4) [
]. The major DNMT1/PCNA/UHRF1 complex
is mainly formed and recruited during the S phase of cell
cycle, but additional DNMT1/TFs interactions are
associated with different phases. For example, DNMT1 could
interact predominantly with SP1 during G1 and G2 phases,
while DNMT1/P53 and DNMT1/E2F3 interactions were
mainly observed during G2 and S/G2 phases respectively in
U251 cells [
DNMT1/P53 Activation of the TF P53 increased the
expression of a large group of genes while surprisingly, a
fraction of genes with a P53 box where repressed [
ternary repressor DNMT1/P53/HDCA1 complex was able
to repress, in a DNA methylation manner, the expression
of specific genes (e.g., SURVIVIN) by catalyzing both
DNA methylation and histone deacetylation, on specific
DNA loci recognized by P53. Repressive capacities of
DNMT1/P53-including complexes are also controlled by
additional regulators. Indeed, following DNA damage,
DNMT1/P53-mediated silencing of the SURVIVIN gene
was dependent of NBS1 (Nijmegen breakage syndrome)/
DNMT1 interaction [
]. Likewise, the P53-dependent
repression of CDC25C required SP1 (specificity
protein1)/P53 interaction, allowing the recruitment of DNMT1
close to SP1 and P53 response elements [
mSIN3a and P53/HDACs interactions were also involved
in P53-mediated gene silencing. Interestingly, the indirect
interaction of the mutated P53 with DNMT1/HDAC1/
HDAC2/MeCP2 complex was also implicated in ERα
(estrogen receptor: ESR1) silencing in MDA-MB-468BC
cells, suggesting that abnormal TFs may mediate specific
DNA methylation in cancers [
DNMT1/RUNX1-MTG8 Modified TFs (punctual
mutations, chimerical proteins, and specific post-translational
modifications) or an increase expression of a particular TF
may contribute to generate new TF/DNMTs interactions or
to favor pre-existing interactions in pathologic tissues and
therefore to induce specific DNA methylation. Indeed, the
t(8;21)(q22.q22) translocation, which was frequently
observed in acute myeloid leukemia, induces the formation of
the chimerical protein RUNX1 (runt-related transcription
factor 1, also called AML1 or CBFA2) -MTG8 (ETO,
CBFA2T1) which mimics an oncogenic TF. In normal cells,
RUNX1 bound to the enhancer sequence TGT/CGGT
whereas MTG8 is a transcriptional repressor able to interact
with other co-repressors. Direct or indirect DNMT1/
RUNX1-MTG8 interaction was observed in a complex
including the co-repressors HDACs, mSIN3a and N-Cor and
all components synergistically silenced some specific genes
(e.g., IL-3) [
STAT3/DNMT and cancer The repression of the PTPN6
gene was mediated by the recruitment of DNMT1/STAT3
(phosphorylated)/HDAC1 complex on STAT3 boxes n
PTPN6 promoter [
]. Moreover, STAT3 acetylation
(K685ac), which increased in melanoma, triple negative BC,
or in colon cancer compared to normal tissue, was also
associated to a specific profile of DNA methylation. The
mutated STAT3 K685R inhibited DNMT1/STAT3
interaction and restored the expression of these genes.
Indeed, specific inhibition of DNMT1/STAT3 interaction
using peptides competitors also significantly decreased
glioma-cell proliferation [
HESX/DNMT1 During development, many genes are
thinly and kinetically regulated. One of the TF,
controlling this timing is HESX1 (HESX homeobox 1), which
mediates the repression of HESX1-target genes by both
recruiting co-repressors (such as TLE1 or N-Cor) and by
specific DNA methylation in a HESX1/DNMT1
Indirect interaction with TF The target of
DNMT1including complexes on specific TF-response elements
can also be mediated by indirect interactions with TFs.
Indeed, the presence of the transcriptional repressor
DAXX lead to the silencing of ReIB target genes which
are normally activated by this TF. This DNA methylation
repression is mainly mediated by the indirect recruitment
of DNMT1 via the DAXX/DNMT1 and DAXX/RelB
interactions and is completed by the further recruitment of
HDAC2 on these promoters [
]. Similarly, P53 was also
required for the recruitment of DAXX and DNMT1 on
RASSAF1A promoter and its methylation in lymphoblastic
Specific recruitment of DNMT3 and DNMT3B by TFs
TFs are also capable of inducing the specific recruitment of
DNMT3A and DNMT3B in DNA. DNMT3A can interact
with P53 (via its C-ter) leading to the repression of
P53regulated genes (e.g., p21) although the existence of P53/
DNMT3A-mediated de novo methylation was not clearly
]. On the opposite, in the lymphocytes
lineage, the recruitment on purine-rich sequences of the
DNMT3A/DNMT3B/PU.1 complex (which requires the
interaction of the ETS domain of PU.1 with the ATRX
domain of DNMT3s) induced the DNA methylation of
PU.1-regulated genes such as p16(INK4a). Silencing of the
target genes was then completed by histone modifications
mediated by the PU.1/mSIN3a/HDAC/MeCp2 complex
]. During transformation of HS cells following
overexpression of the oncoprotein EVI1, DNMT3A and DNM
T3B could interact with EVI1 and therefore specifically
methylate the miRNA-124-3 promoter [
interaction of DNMT3A with ISGF3 or AP2a, and DNM
T3B with CREB1, ELK1 or PPARg may be important for
the repression of genes normally controlled by these TFs.
For example, inhibition of the DNMT3A/ISGF3ϒ
interaction increased the response to temozolomide in glioma
]. A direct interaction of c-MYC with DN
MT3A and DNMT3B was responsible for the recruitment
of DNMT3 on a c-MYC box in CCND1 promoter, in a
MIZ1-dependent manner. On the opposite, in the absence
of MYZ1, c-MYC recruitment on c-MYC response element
induced the transcriptional activation of CCND1 [
Similarly, the ZEB-1 (an epithelial to mesenchymal
transition-TF)/HDAC1/DNMT3A complex has been
involved in the specific repression of Neurogenin 3 gene
]. The same complex was also involved in the ESR1
gene repression following its recruitment on E2-boxes
identified by ZEB-1 [
]. In leukemia, the frequent
translocation of t(15;17) leads to the formation of the PML-RARα
fusion protein. Recruitment of PML-RARα on RARβ2
promoter induced the recruitment of DNMT1 and DNMT3A
by direct interactions [
E2F family and DNMTs recruitment
The E2F family members regulate the expression of many
genes during cell cycle by interacting to E2F response
elements. Interaction of E2F6 with DNMT3B but not with
DNMT3A was required for specific homeotic silencing
]. The recruitment of the DNMT1/HDAC1/RB/
E2F1 complex was dependent of the presence of E2F
response elements, and this complex controlled the
expression of genes normally activated during middle G1 to late S
phase . The DNMT1/p130-RB2/E2F4/E2F5/HDAC1/
SUV39H complex was also involved in silencing of the ER-a
]. Moreover, the LANA antigen (Kaposi’s
sarcoma-associated herpes virus LANA), which indirectly
activates some genes in an E2F activation manner, could also
specifically silence other genes (e.g., 13H CADHERIN) by
inducing LANA/DNMT3A/E2F interaction-mediated de novo
Redundancy or specificity of TF/DNMTs interactions
Little is currently known about the specificity of each
DNMT for one or another protein partner. Although
some redundancy may explain that invalidation of one
DNMT could sometimes be balanced by another one
(P53 can interact with both DNMT1 and DNMT3A),
the analysis of cell-validated or in vitro putative TF/
DNMT interactions revealed that some interactions are
specific to one DNMT [
]. As illustrated in Fig. 5,
29 TFs or co-repressors tested, potentially interact with
the 3 DNMTs (e.g., the MBD protein MeCP2 or the TFs
GATA1, HAND1, and HAND2), while others are
restricted to one or two of these enzymes (9 only with
DNMT1, 17 only with DNMT3A, 5 only with DNMT3B,
10 with both DNMT1 and 3a, 5 with both DNMT1 and
3b, 9 with both DNMT3A and 3b). We could not
predict interaction with any DNMT for 15 additional TFs
tested. One interesting example is the E2F family. E2F5
can potentially interact with all three DNMTs while
E2F4 and E2F6 can only interact with DNMT1 and DN
MT3B, respectively. Specific pattern of expression of
some TFs may limit their role on DNA methylation to
specific tissues. For example, the putative DNA
methylation activity of the DNMT3A/NR5A2 complex is
probably confined to pancreatic cells, since NR5A2 is more
abundant in pancreas. DNMT3L which is catalytically
Aliases (source NCBI), full names, and targets are summarized. Protein functions are calssified with different colors: gray: scaffold and connector proteins; yellow:
proteins involved in DNA replication and cell division; salmon: proteins interacting with methylated DNA; green: histone methylases or histones demethylases;
purple: histone deacetylase; brown: DNA repair proteins
inactive is also capable of interacting with TFs which are
similar or different from TFs interacting with DNMT3A
and/or DNMT3B (Fig. 5) . Moreover, the
recruitment of a DNMT3L/TF-including complex on a specific
locus may also regulate the specific methylation of this
sequence by mediating the further recruitment of
DNMT3A or DNMT3B. This has been illustrated by the
specific methylation of the promoter TRAF1 by the
indirect recruitment of DNMT3A and DNMT3B via the
Epigenetic silencing appears thinly regulated and
orchestrated and frequently requires the presence of several
DNMT-including complexes, polycomb proteins and
HDACs, interacting together in a specific kinetic. A list
of the main repressors directly or indirectly interacting
with DNMTs is proposed in Table 1. For example,
epigenetic silencing of the NY-ESO1 gene in glioma and
mesothelioma cells required the sequential recruitment
of three independent complexes: (i) HDAC1/mSIN3a/
NCOR complex which deacetylates the promoter, (ii)
DNMT3B/HDAC1/EGR1 complex which induces a local
DNA methylation and increases histone deacetylation,
and (iii) DNMT1/PCNA/UHRF1/G9a complex which
maintains DNA methylation and introduces the
H3K9me2 repressive mark [
]. The question related
to the switch between transcriptional to “repression
activity” of a TF is still unclear. Contrary to TF-mediated
maintaining of DNA methylation in promoters, already
repressed, the role of TF in specific TF-mediated de
novo methylation is crucial for the control of gene
expression. Ratio between free TF versus TF-DNMT
complex or association with additional co-repressor in
TF-Dnmt / TF ratio
multi-protein complexes could determine the nature of
the activity (activator or “repressor”) of each TF able to
associate with a DNMT. For example, it has been
proposed that, following DNA damages, an increase of P53
content could incline towards the P53/DNMT1
interaction and DNA methylation. Indeed, PU.1/DNMT3A/
DNMT3B interactions may be favored by high amounts
of PU.1 in leukemia [
]. A second hypothesis could
incriminate the accessibility of the TF-response element:
Detachment of a free TF from its response element may
allow the specific recruitment of the DNMT/TF
complex. Finally, post-translational modifications of TFs
could also regulate the binding capacities and stability of
TFs/DNMT-including complexes and may involve
enzymes required for histones modifications (STATs,
HDACs) (Fig. 6). The understanding of these
mechanisms will constitute a great challenge to determine the
kinetic of the events, the possible correlations between
TF expressions and specific gene repressions, and/or the
existence of specific DNA sequences that could be more
sensible to TF-mediated methylation.
aa: Amino acids; BAH domains : Adjacent homology domain; BC: Breast
cancer; BER: Base excision repair; CFP1: CysxxCys finger protein 1;
DNMT: DNA methyl transferase; ERα: Estrogen receptor; EZH2: Enhancer of
zest homolog 2; GCNF: Germ cell nuclear factor; HBX: Hepatitis B virus x
protein; hCAP: Human chromosome associated protein; HESX1: HESX
homeobox 1; HMT: Histone methyl transferase; HP1: Heterochromatin
protein-1; ICF: Immunodeficiency, centromeric instability, and facial
dysmorphism; LSD1: Lysine-specific demethylase 1A; LSH: Lymphoïd-specific
helicase; MBD: Methyl CpG-binding domain protein; miRNA: MicroRNA;
mSIN3A: SIN3 transcription regulator family member A; NBS1: Nijmegen
breakage syndrome; NSPc1: Nervous system polycomb; PcG: Polycomb
group; PCNA: Proliferative cell nuclear antigen; PKC: Protein kinase C;
RESEs: Ras epigenetic effectors; RFTS: Replication focus targeting sequence;
RUNX1: Runt-related transcription factor 1; SETDB1: SET domain bifucarted 1;
SP1: Specific protein; SRA: SET and RING; TRD: Transcription repression
domain; UHRF1: Ubiquitin-like PHD and RING finger domain 1;
WRNp: Werner protein
This work was supported by the University of Franche-Comté, “Ministère de
l’Enseignement Supérieur et de la Recherche” (MESR) and fundings from
CCIR-GE “Ligue Contre le Cancer” and “Région de Franche-Comté”.
Availability of data and materials
EH wrote the paper and MBG, PP, RDM, and PFC revised the paper. All
authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1INSERM unit 1098, University of Bourgogne Franche-Comté, Besançon,
France. 2EPIGENExp (EPIgenetics and GENe EXPression Technical Platform),
Besançon, France. 3INSERM unit S1232, University of Nantes, Nantes, France.
4Institut de cancérologie de l’Ouest, Nantes, France. 5REpiCGO (Cancéropole
Grand-Ouest), Nantes, France. 6EpiSAVMEN Networks, Nantes, Région Pays de
la Loire, France.
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