Biology Reference
In-Depth Information
enzyme has a repressive effect on gene function, but its function
in vivo
or
whether Smyd5 integrates in the heterochromatin feedback loop described
earlier has not been addressed (
Stender et al., 2012
).
Loss-of-function strategies of the corresponding methyltransferases have
been used in order to study the function of histone methylation of H3K9 and
H4K20. However, in most cases, they have not been deleted specifically in
the maternal germ line and therefore the embryos analyzed carry maternal
contribution of these methyltransferases, since their mRNAs are present
in the oocyte (
Hamatani, Carter, Sharov, & Ko, 2004; Wang et al., 2004;
Zeng & Schultz, 2005
). A role for H3K9 and H4K20 methylation during
the earliest stages of preimplantation development has therefore not been
addressed directly.
Double null embryos for G9a showhigh lethality between embryonic day
(E) 9.5 and E12.5, with many morphological defects and loss of weight com-
pared to heterozygous littermates. This result showed that G9a is necessary
for proper embryonic development and thus that methylation of H3K9 in
euchromatic regions is functionally essential for mid-gestation (
Tachibana,
Sugimoto, Fukushima, & Shinkai, 2001; Tachibana et al., 2002
). Further-
more, conditional KO of G9a in the mouse germ line showed that it is essen-
tial for meiotic prophase progression and is involved in gametogenesis
(
Tachibana et al., 2007
). Finally, conditional KO of G9a in CD4(
รพ
) T cells
(
Lehnertz et al., 2010
) or adult neuronal cells (
Schaefer et al., 2009
) in adult
mice showed a functional role for the reduction of H3K9me2 in immune and
cognitive abnormalities. Interestingly, studies have demonstrated that KO of
GLP has the same phenotype as G9a
/
during embryogenesis. This is some-
what expected since GLP and G9a can form heterodimeric structures and
might positively regulate each other's catalytic activity: indeed, KO of
GLP causes a reduction not only in H3K9me3 but also in H3K9me1 and
H3K9me2 in euchromatic regions, resulting in relocalization of HP1
(
Tachibana et al., 2005
). Deletion of the SET domain of ESET results in
embryonic death around peri-implantation with defects in ICM formation
and inability to derive ES cell lines (
Dodge et al., 2004
). RNAi-mediated
silencing of ESET in murine ES cells causes the differentiation of these cells
into trophoblastic lineage, thus demonstrating a potential role in restricting
the fate of ICM cells during development (
Yuan et al., 2009
).
Single KO of either Suv39h1 or Suv39h2 seems not to have an effect on
development, but double null mice for Suv39h1 and Suv39h2 show
increased prenatal lethality than wild-type mice as well as genome instability
upon DNA damage and missegregation during meiosis (
Peters et al., 2001
).
