Biology Reference
In-Depth Information
Several lessons have been derived concerning L1 expression from trans-
genic mouse models. Transgenic animals containing L1 expressed from its native
promoter supported L1 expression in testis and ovaries (Ostertag
, 2002).
Pol-II driven L1 was also expressed in kidney, lung, intestine, liver, and brain
(Ostertag
et al.
, 2002). RT-PCR analysis of germ cell fractions such as pachytene
spermatocytes, round spermatids, and condensing spermatids demonstrated L1
expressed with varying efficiency within these three cell types (Ostertag
et al.
,
2002). Another transgenic mouse model of human L1 driven by the mouse
pHsp70-2 promoter demonstrated very strong positional effect of the transgene
integration site on retrotransposition (Babushok
et al.
, 2006). This observation
suggested that L1 transgene expression in the transgenic mouse model can be
significantly affected by its specific location, consistent with the reports of
positional effects on the expression of endogenous L1 loci (Lavie
et al.
, 2004).
Transgenic mouse and rat models of human and mouse L1 retrotransposition
driven by their respective endogenous promoters demonstrated L1 mRNA pres-
ence in both germ cells and embryo. In these models retrotransposition events
occurred in embryogenesis creating nonheritable somatic mosaicism (Kano
et al.
,
2009). In contrast to the previous models, a transgenic animal expressing a single
copy of the synthetic mouse L1 element demonstrated significantly higher retro-
transposition compared to retrotransposition frequencies detected in animals
containing multiple integrated copies of the same L1 transgene (An
et al.
,
2006, 2008). Retrotransposition in a transgenic mouse model was also reported
to take place in the mouse brain strongly supporting L1 expression in normal
brain cells (Muotri
et al.
, 2005). Analysis of the methylation status of endoge-
nous L1 promoters coupled with detection of
et al.
de novo
L1 retrotransposition
events (Coufal
, 2009) in normal human brain produced results consistent
with ongoing expression of endogenous L1 elements in human brain cells. More
comprehensive analysis of endogenous L1 mRNA expression in normal human
tissues and adult stem cells demonstrated that the majority of the examined
human tissues support endogenous L1 mRNA expression (Belancio
et al.
,
2010b). However, the abundance of the total L1-related transcripts and the
amount of the full-length L1 mRNA varies significantly among tissues. This
variation appears to be at least in part influenced by the tissue-specific differences
in the efficiency and pattern of L1 mRNA processing (Belancio
et al.
, 2010b).
The same is true for human cancer cell lines where the amount of the full-length
L1 mRNA is dictated by the efficiency of L1 mRNA splicing and premature
polyadenylation (Belancio
et al.
, 2010b). Somatic endogenous L1 expression
combined with the lack of obvious restrictions for somatic retrotransposition
(An
et al.
, 2006) and L1-induced
double-strand DNA break (DSB) formation in normal cells (Belancio
et al.
, 2006, 2008; Kano
et al.
, 2009; Kubo
et al.
.)
suggests that ongoing L1-induced DNA damage is likely to take place in somatic
tissues. Because of the reported variation in the L1 promoter strength in different
et al
