An endogenous retroviral long terminal repeat is the dominant promoter for human β1,3-galactosyltransferase 5 in the colon

Abstract

LTRs of endogenous retroviruses are known to affect expression of several human genes, typically as a relatively minor alternative promoter. Here, we report that an endogenous retrovirus LTR acts as one of at least two alternative promoters for the human ␤1,3-galactosyltransferase 5 gene, involved in type 1 Lewis antigen synthesis, and show that the LTR promoter is most active in the gastrointestinal tract and mammary gland. Indeed, the LTR is the dominant promoter in the colon, indicating that this ancient retroviral element has a major impact on gene expression. Using colorectal cancer cell lines and electrophoretic mobility-shift assays, we found that hepatocyte nuclear factor 1 (HNF-1) binds a site within the retroviral promoter and that expression of HNF-1 and interaction with its binding site correlated with promoter activation. We conclude that HNF-1 is at least partially responsible for the tissue-specific activation of the LTR promoter of human ␤1,3-galactosyltransferase 5. We demonstrate that this tissue-specific transcription factor is implicated in the activation of an LTR gene promoter.

Comparative Analysis of Retroviral and Native Promoters Driving Expression of β1,3-Galactosyltransferase β3Gal-T5 in Human and Mouse Tissues

“…In competitive EMSAs (Fig. 6C), formation of the major complex was prevented by the addition of the HNF-1 binding sequence of the SIF3 oligonucleotide as well as by an antibody specific to HNF-1, indicating the presence of an HNF-1 binding site, as reported for the LTR promoter (6,7). To directly compare these two promoters, competitive EMSAs were performed using both sequences (Fig.…”

“…Type B and C 5Ј-UTR transcripts begin with exon 1B and 1C, respectively, and both comprise the two main splice variants described above. Exon 3 is present at the 3Ј-end of all of the novel 5Ј-UTR-containing transcripts, as is true for the LTR-and brain-derived 5Ј-UTR mRNAs (1,7).…”

“…In some colon cancer cells, the first exon (exon 1) in the 5Ј-UTR of the ␤3Gal-T5 transcript is under the control of a promoter located ϳ150 bp upstream and regulated primarily by the transcription factors HNF-1 and Cdx (6). Interestingly, the entire exon 1, as well as the HNF-1/Cdx binding motif, belongs to a retroviral long terminal repeat (LTR) sequence that is the dominant promoter for the ␤3Gal-T5 gene in the colon but is inactive in other tissues where ␤3Gal-T5 is expressed (7).…”

Repeated Recruitment of LTR Retrotransposons as Promoters by the Anti-apoptotic Locus NAIP During Mammalian Evolution

“…An example is the carbonic anhydrase gene (CA1), where an ancestral LTR drives erythroid-specific expression of the orthologs [6]. The more commonly documented situation is where a lineage-specific LTR acts as a gene's promoter in one species but not the other, as illustrated by the b3GALT5 gene in human [31] and various mouse genes including Spindlin [32]. The results of this study illustrate a third evolutionary scenario not previously reported: distinct LTR elements specific to the primate or rodent lineages have independently assumed roles as promoters for the NAIP orthologs.…”

“…ORR1s and MTs are rodent-specific LTR families within the MaLR superfamily [24], represented by .400,000 copies in the sequenced mouse genome [2]. The fact that the ORR1E LTR is the primary promoter for these genes is unusual, considering LTRs most often function as tissue-specific or alternative promoters [7,8,31,32,37]. Another intriguing finding is the fact that an MTC LTR has inserted into the mNaipe/f progenitor and behaves as a secondary promoter.…”