Promoters and transcription factors - Human Gene Evolution - page 243

Wellstein, 1998). This HERV element has been shown to drive the expression of
the PTN gene in trophoblasts and in choriocarcinoma cell lines (Schulte et al .,
1996). The HERV sequence is also present in the Ptn genes of chimpanzee and
gorilla but not in that of the rhesus macaque indicative of a genomic insertion
event which occurred after the divergence of the great apes from the Old World
monkeys some 23 Myrs ago. The expression of the human HLA-DRB6 gene is
driven by the LTR of a Mouse Mammary Tumor Virus (MMTV)-like sequence
which substituted for the original promoter upon insertion (Mayer et al ., 1993).
Since this MMTV-LTR is also present in the macaque, the insertion event must
have occurred >23 Myrs ago. Finally, Feuchter et al . (1992) have employed a sys-
tematic screening strategy to demonstrate that the expression of a number of
other human cellular genes may be influenced by endogenous retroviral ele-
ments; these include the cell division cycle 4-like ( CDC4L ) gene.
Retroviral insertion may affect gene expression even if the element is inserted
outwith the promoter region. One example is the LTR of an RTV L -H element
which is present in the 3 UTR of a human placentally expressed gene (termed

'PLT' by the authors, Goodchild et al ., 1992); the Plt mRNA undergoes alterna-
tive splicing at its 3

end with polyadenylation occurring within the LTR in one
of the transcripts. This sequence is present in the Plt genes of the great apes and
Old World monkeys and therefore must have been inserted prior to the diver-
gence of these groups.
An LTR of an ERV9 element has been found at the 5 boundary of the human

-globin ( HBB ; 11p15) gene locus control region (LCR; see Chapter 1, section
1.2.8) just upstream of the DNAse I-hypersensitive site HS5 (Long et al ., 1998).
This LTR is composed of 14 tandem repeats containing recurring GATA,
CACCC, and CCAAT motifs that are potentially capable of binding GATA-bind-
ing factor, BKLF/TEF2 and C/EBP transcription factors respectively. The orthol-
ogous sequence in gorilla has only five repeats whilst the repeat number is
polymorphic in humans. Reporter gene studies have demonstrated that this LTR
possesses both enhancer and promoter activity in erythroid cells (Long et al .,
1998). Moreover, in erythroid cells, the LTR activates transcription of the down-
stream retroviral R and H5 regions and of genomic regions still further down-
stream (Long et al ., 1998). The HS5 LTR may therefore play a role in regulating
the transcription of the human -globin LCR (which is preferentially transcribed

in erythroid cells) which may in turn serve to open up the chromatin structure of
the -globin gene domain.

Retroviral insertions have also influenced gene expression in other mammalian
species. Thus the promoter of the rat oncomodulin gene (human counterpart
OCM ; 7p13-p11) contains a long terminal repeat of an intracisternal A particle
(IAP, a family of endogenous retroviral elements) which has been recruited to per-
form a gene regulatory function (Banville and Boie, 1989). Since the mouse lacks
the integrated IAP element, the IAP insertion must have occurred after the diver-
gence of the two rodent species 40 Myrs ago (Banville et al ., 1992).

LINE elements. LINE elements may also have served as mobile regulatory
sequences altering the expression of target genes. They have a tendency to acquire
promoter sequences from non-LINE sources, with different sequence lineages