Abstract
Long interspersed element-1 (L1) is a transposable element that can move within the genome, potentially leading to genome diversity and modified gene function. Although L1 activity in somatic cells is normally suppressed through DNA methylation, some L1s are activated in tumors including colorectal carcinoma. However, how L1-retrotransposition (L1-RTP) is involved in gastrointestinal disorders remains to be elucidated. We hypothesized that L1-RTP in somatic cells might contribute to colitis-associated cancer (CAC). To address this, we employed an experimental model of CAC using transgenic L1-reporter mice carrying a human L1-EGFP reporter gene. Mice were subjected to repeated cycles of colitis induced by administration of dextran sodium sulfate (DSS) in drinking water with injection of carcinogen azoxymethane (AOM). L1-RTP levels were measured by a quantitative polymerase chain reaction targeting the newly inserted reporter EGFP in various tissues and cell types, including samples obtained by laser microdissection and cell sorting with flow cytometry. DNA methylation levels of the human L1 promoter were analyzed by bisulfite pyrosequencing. AOM+DSS-treated mice exhibited significantly higher levels of L1-RTP in whole colon tissue during the acute phase of colitis when compared with control naïve mice. L1-RTP levels in whole colon tissue were positively correlated with the histological severity of colitis and degree of neutrophil infiltration into the lamina propria (LP), but not with tumor development in the colon. L1-RTP was enriched in LP mesenchymal cells rather than epithelial cells (ECs), myeloid, or lymphoid cells. DNA methylation levels of the human L1 promoter region showed a negative correlation with L1-RTP levels. L1-RTP was absent from most tumors found in 22-week-old mice. In conclusion, we demonstrated that L1-RTP was induced in the mouse CAC mucosa in accordance with the acute inflammatory response; however, retrotransposition appears not to have direct relevance to colitis-induced cancer initiation.
Highlights
Long interspersed element -1 (L1) is a transposable element that can move within the genome to induce gene deletions, inversions, and insertions, potentially leading to genome diversity as well as altering gene function [1,2]
L1 activity is normally suppressed in somatic cells through epigenetic mechanisms, such as DNA methylation, some L1s are activated by environmental factors including carcinogens and proinflammatory compounds [5,6,7,8]
We found that L1-RTP was significantly increased during the acute phase in the AOM+dextran sulfate sodium (DSS) colitis group, but not in tumors or in the background mucosa of tumor-bearing colons (Fig. 1B)
Summary
Long interspersed element -1 (L1) is a transposable element that can move within the genome to induce gene deletions, inversions, and insertions, potentially leading to genome diversity as well as altering gene function [1,2]. We successfully obtained colon tumors from 22-week-old mice after four injections of AOM and four cycles of DSS colitis. To examine the induction of L1-RTP, we first obtained whole colon tissue from each group of mice during the tumor phase (22-week-old) or during the acute phase after the first administration of DSS (8-week-old).
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