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BOX 8.1 Interplay between H3K9 and DNA methylation
Generally, DNA methylation ( Jones, 2012 ) and H3K9 methylation serve similar
purposes in long-term silencing. However, a direct (inter-)dependence between
these two silencing mechanisms is not always clear. DNA demethylation for the
generation of induced pluripotent stem cell is critical, as it can be enhanced with
inhibitors like azacytidine ( Yamanaka & Blau, 2010 ). Interestingly, a screen for the
identification of barriers against in vitro reprogramming identified Suv39h1
( Onder et al., 2012 ), suggesting that losing DNA methylation and H3K9me3 is
required for reprogramming. On the other hand, MEFs deficient for Suv39h1/2
show a concomitant loss of H3K9me3 and DNAme at PCH ( Lehnertz et al.,
2003 ). This decrease could be a consequence of the loss of HP1a binding. Indeed,
artificial targeting of HP1 to euchromatic genes allows recruitment of DNMT1 and
transcriptional silencing ( Smallwood, Estève, Pradhan, & Carey, 2007 ). G9a
appears to act synergistically with DNMTs to mediate de novo epigenetic silenc-
ing. Dnmt3a/b associates with G9a through its ankyrin domains to silence key
pluripotency factors like Oct3/4 and suppresses proviruses ( Epsztejn-Litman
et al., 2008; Leung et al., 2011 ). G9a also interacts directly with DNMT1 to form
a ternary complex with PCNA required for maintaining DNA and histone meth-
ylation on rDNA repeats throughout replication ( Estève et al., 2006 ). However,
DNA methylation and G9a-mediated H3K9 methylation seem to occur mostly
as two parallel pathways ( Tachibana et al., 2008 ), because most of the DNA meth-
ylation defects seen in G9a / ESCs can be rescued by a catalytically dead enzyme
( Dong et al., 2008 ). DNMT1 associates with Np95 (also known as Uhrf1 or ICBP90)
( Sharif et al., 2007 ), which has the ability to bind hemimethylated DNA through
its SET and RING finger-associated (SRA) domain and H3K9me2/3 through its
tandem tudor domain. Np95 can bind H3K9me2/3 regardless of the presence
of H3S10P. Insensitive to the phosphomethyl switch ( Fischle et al., 2005 ), Np95
provides a way of maintaining DNA methylation during mitosis ( Rothbart et al.,
2012 ). This bridging protein would then allow DNMT1 to prevent the loss of
DNA methylation states during critical steps of the cell-cycle.
Such coordination between DNA replication and maintenance of histone and
DNA methylation seems to apply for PCH through the association of the methyl-
CpG binding protein MBD1 and SETDB1 to replication forks ( Sarraf & Stancheva,
2004 ). Indeed, it has been suggested that SETDB1-mediated H3K9me1 would serve
as a substrate for the Suv39h enzymes to restore H3K9me3 on PCH as replication is
ongoing ( Dambacher, Hahn, & Schotta, 2010 ). SETDB1 associates with the corepres-
sor KAP1 (also known as Trim28/Tif1b) ( Schultz et al., 2002 ). Biochemical studies
showed that KAP1 is in a complex with remodeling enzymes (Mi2a), DNA met-
hyltransferases (DNMT1, DNMT3a, DNMT3b), KMT (SETDB1), HP1, and KRAB-ZNF
proteins (for review see Iyengar & Farnham, 2011 ). KAP1 repressive complex was
shown to be implicated in the overall silencing of euchromatic genes,
retrotransposons, and imprinted control regions (ICRs) during development
Continued
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