PMC:2725788 / 26456-30040 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/2725788","sourcedb":"PMC","sourceid":"2725788","source_url":"http://www.ncbi.nlm.nih.gov/pmc/2725788","text":"3.1.3. Methylation of ERVWE1 LTRs and associated MaLR LTR suggests a regional control\nBy definition, ERVWE1[5′LTR] and ERVWE1[3′LTR] belong to the same proviral unit, but appeared differentially methylated in villous placenta. This unmethylation of the 5′LTR corresponds with its promoter function in placenta, as reported previously.39 The 3′LTR methylation in return may prevent a local competition with ERVWE1 5′LTR for promoter activity as well as a 3′LTR-derived transcriptional interference with the nearby antisense-oriented ODAG/GATAD1 gene.46 Such a differential methylation has been observed for HTLV-152 and HIV-1 proviruses during viral latency.53 For these two retroviruses, however, methylation favored repression of the 5′LTR promoter activity as the 5′LTR was methylated and the 3′LTR was not. This suggests different methylation features for exogenous/pathogenic and endogenous/domesticated proviruses but possibly a conserved strategy to prevent methylation spreading on both proviral LTRs, like the use of boundary elements as hypothesized for HTLV-1.52 The CTCF protein is a factor able to create boundaries between methylated and unmethylated genomic domains.54 Interestingly, two domains containing potential binding sites for CTCF were identified within ERVWE1 provirus (www.essex.ac.uk/bs/molonc/spa.htm), respectively, downstream from the 5′ LTR and upstream from the 3′ LTR region that we found methylated. Further investigations are required to ascertain CTCF functional relevance in the context of proviruses. Nevertheless, it appears that methylation might be regionally controlled and linked either to the genomic environment or to the LTR function.\nThe upstream flanking sequence of three out of the four HERV-W LTRs was amplified along with the respective LTRs. Except for one clone in the villous placenta tissue, the MaLR[LTR] directly upstream from ERVWE1 presented the same methylation profiles as the ERVWE1[5′LTR], i.e. either unmethylated, partially methylated or highly methylated (for methylation values, see Fig. 2B). In contrast, the CpG sites contained within the ∼200 bp of the env gene co-amplified with ERVWE1[3′LTR] appeared systematically highly methylated, including those in the villous placenta (with 92.5% of methylation level), despite a lower methylation (68%) of the 3′LTR in this tissue (Fig. 2C). Finally, methylation levels between HW_4[5′LTR] and the upstream MER114[LTR] part were similar in PBL and placental fibroblasts, but in the villous placenta, HW_4[5′LTR] methylation level was much lower (40%) than the MER114 (70%) (Fig. 2D). Thus, except for ERVWE1[5′LTR] and the upstream MaLR[LTR], there was no clear correlation between the methylation of the HERV-W LTRs and their flanking sequence. Reiss et al.38 also recently concluded that the hypomethylation of HERV-E LTRs acting as placenta promoters of cellular genes, when compared with random LTRs, cannot be explained by a difference in methylation of their flanking sequences, irrespective of its nature—repeated element or not.\nThe MaLR[LTR] and the ERVWE1[5′LTR] elements have been earlier demonstrated to be co-opted and to specifically control ERVWE1 placental expression.43,46 Thus, although belonging to distinct LTR types, their shared unmethylation status in placenta could be linked to their involvement in the regulation of Syncytin-1 transcription. Likewise, the heavy methylation of both LTRs in non-placenta cells supports a repression process outside placenta. Overall, these results are compatible with ERVWE1 env regulation as a bona fide gene.45","divisions":[{"label":"Title","span":{"begin":8,"end":86}}],"tracks":[{"project":"2_test","denotations":[{"id":"19561344-16427621-25963818","span":{"begin":335,"end":337},"obj":"16427621"},{"id":"19561344-16176588-25963819","span":{"begin":550,"end":552},"obj":"16176588"},{"id":"19561344-12186921-25963820","span":{"begin":612,"end":615},"obj":"12186921"},{"id":"19561344-17034647-25963821","span":{"begin":658,"end":660},"obj":"17034647"},{"id":"19561344-12186921-25963822","span":{"begin":1071,"end":1073},"obj":"12186921"},{"id":"19561344-16989720-25963823","span":{"begin":1181,"end":1183},"obj":"16989720"},{"id":"19561344-17617638-25963824","span":{"begin":2772,"end":2774},"obj":"17617638"},{"id":"19561344-15507602-25963825","span":{"begin":3198,"end":3200},"obj":"15507602"},{"id":"19561344-16176588-25963826","span":{"begin":3201,"end":3203},"obj":"16176588"},{"id":"19561344-14757826-25963827","span":{"begin":3582,"end":3584},"obj":"14757826"}],"attributes":[{"subj":"19561344-16427621-25963818","pred":"source","obj":"2_test"},{"subj":"19561344-16176588-25963819","pred":"source","obj":"2_test"},{"subj":"19561344-12186921-25963820","pred":"source","obj":"2_test"},{"subj":"19561344-17034647-25963821","pred":"source","obj":"2_test"},{"subj":"19561344-12186921-25963822","pred":"source","obj":"2_test"},{"subj":"19561344-16989720-25963823","pred":"source","obj":"2_test"},{"subj":"19561344-17617638-25963824","pred":"source","obj":"2_test"},{"subj":"19561344-15507602-25963825","pred":"source","obj":"2_test"},{"subj":"19561344-16176588-25963826","pred":"source","obj":"2_test"},{"subj":"19561344-14757826-25963827","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#afec93","default":true}]}]}}