Biology Reference
In-Depth Information
Promoter function can be significantly regulated through the promoter
methylation and epigenetic modifications. Utilization of promoter methylation to
repress TE expression is thought to be a common cellular defense mechanism
against TE-associated damage [reviewed in Yoder
, 1997]. The promoters of
the majority of the L1 and Alu loci are hypermethylated in normal cells (Alves
et al.
et al.
, 1996; Florl
et al.
, 1999; Hata and Sakaki, 1997; Lees-Murdock
et al.
, 2003;
Takai
, 1993; Tsutsumi, 2000). The importance of the
maintenance of their methylation status is confirmed in the transgenic mice
deficient for DnmtL3 protein required for upholding of DNA methylation
(Bourc'his and Bestor, 2004). Significant upregulation of the expression of endog-
enous retroviruses and L1 elements accompanied the lack of proper DNA meth-
ylation in these transgenic animals. The effect of deficient methylation of genomic
DNA on the expression of SINEs has not been tested in this experimental model.
Retrotransposon methylation is also regulated by Piwi family members MILI and
MIWI2 (Kuramochi-Miyagawa
et al.
, 2000; Thayer
et al.
, 2008). Despite hypermethylation, there is a
small portion of loci, at least in the case of L1 elements that escape methylation
(Coufal
et al.
, 2009). This is consistent with the ongoing endogenous L1 expres-
sion in human somatic tissues (Belancio
et al.
, 2010b). Methylation control of TE
transcription is likely released during the course of embryogenesis when methyl
groups are removed in the global manner to reestablish genome methylation
(Hellmann-Blumberg
et al.
, 1993). The loss of L1 and Alu promoter methylation
is also reported in the majority of human cancers (Takai
et al.
et al.
, 2000; Tsutsumi,
2000) and it is routinely used as a marker of transformation.
Once transcription occurs, mRNA processing, specifically as it relates to
L1 expression, plays an important role in dictating how much of the functional
L1 mRNA is made. This processing involves both RNA splicing and premature
polyadenylation at the polyadenylation (pA) sites abundant within L1 ORFs
(Belancio
, 2004; Perepelitsa-Belancio and Deininger,
2003). Both processes exhibit tissue specificity and can lead to the production of
L1-related transcripts that are retrotranspositionally incompetent at the expense
of generation of full-length L1 (Belancio
et al.
, 2006; Han
et al.
, 2010b). This level of control
exists in both normal and cancer cells (Belancio
et al.
, 2010b). It is currently
unclear whether L1 RNA processing in cancer cells changes or remains the same
as it was in the normal cells that they originated from. Nevertheless, mRNA
processing can limit L1 expression by as much as 10-fold among normal cells and
it is responsible for at least fivefold difference in the full-length L1 mRNA
expression between cancer cells that otherwise support the same steady-state
total L1-related mRNA (Belancio
et al.
, 2010b). Similar to L1, SVA elements
also contain functional splice sites that are efficiently used during SVA tran-
scription (Damert
et al.
, 2009). Alu elements that are transcribed by the Pol-III
machinery are observed to be immune to the effects of RNA processing observed
for L1 and SVA elements.
et al.
