PMC:2725788 / 51485-53748 JSONTXT

{"project":"2_test","denotations":[{"id":"19561344-12724415-25963855","span":{"begin":1126,"end":1127},"obj":"12724415"},{"id":"19561344-17080327-25963856","span":{"begin":1267,"end":1268},"obj":"17080327"},{"id":"19561344-16411991-25963857","span":{"begin":1405,"end":1407},"obj":"16411991"},{"id":"19561344-11854637-25963858","span":{"begin":1408,"end":1410},"obj":"11854637"},{"id":"19561344-10692254-25963859","span":{"begin":1652,"end":1654},"obj":"10692254"},{"id":"19561344-18077339-25963860","span":{"begin":1847,"end":1849},"obj":"18077339"}],"text":"4. Conclusions\nOur analyses provide evidence that methylation status of ERVWE1 and other HERV-W LTRs are not related to a family/phylogenetically related process, nor are they systematically correlated with the integration surrounding area. However, they support both tissue- and locus-specific methylation processes for functional LTRs. Still, methylation status seems to differ in relation to the promoter/enhancer role of the LTR or its use as polyadenylation signal. In addition, our results suggest that methylation of HERV LTRs could be involved in the modulation of their activity. Thus, this could be achieved in several ways, through an enhancer/promoter epigenetic co-regulation (e.g. MaLR[LTR] and ERVWE1[5′LTR]) or through a variation in cell proportion with unmethylated LTR (e.g. ERVWE1[5′LTR] in CTs) or else, by targeting preferential CpG sites such as CpGs closed to the TATA box (e.g. ERVFRDE1[5′LTR] in PBL, ERV3[5′LTR] in first trimester CTs). Thus, the selective and temporal unmethylation of ERVWE1[5′LTR] in placenta during the first trimester may allow Syncytin-1-mediated cell differentiation/fusion.6 In contrast, increased methylation at term may limit Syncytin-1 production and consequent cell fusion or putative anti-apoptotic protection7 in accordance with CT limited fusion and higher apoptosis rate. Syncytin-1 transcriptional alterations observed in placental pathologies59,60 could similarly be associated with a temporally deregulated methylation of ERVWE1. Likewise, local methylation of the ERV3 promoter during the first trimester may limit ERV3 Env production and consequent inhibition of early CT proliferation.15 In contrast, hypomethylation of ERV3 promoter in the second trimester or term placenta and in fetal blood cells may allow ERV3 Env expression and consequently, contribute to immunosuppression.13 So, apparently convergent tropism and redundant functions, such as fusion for Syncytin-1 (ERVWE1) and Syncytin-2 (ERVFRDE1) or immunosuppression for Synctin-2 and ERV3-Env, do not strictly match with similar methylation regulation. Sequence determinants and mechanisms involved in LTR methylation need to be further investigated to better understand HERV regulations and deregulations associated with pathologies."}