Hypomethylation and Activation of Syncytin-1 Gene in Endometriotic Tissue

Abstract

Syncytin-1 plays a critical role in the maintenance of normal pregnancy by mediating the formation of syncytiotrophoblasts through a fosugenic action. Encoded by the human endogenous retrovirus envelope gene HERV-W, syncytin-1 trophoblast-specific expression is controlled by epigenetic mechanisms. In non-placental tissues, the syncytin-1 gene is suppressed by hypermethylation in the LTR promoter region. Hypomethylated and activated syncytin-1 gene is found in placental trophoblast lineages and malignant cells. We here demonstrate that while syncytin-1 gene remains silenced in the eutopic endometrium from endometriotic patients, syncytin-1 mRNA and protein are detected in ectopic, endometriotic lesions; particularly the endometrioid glandular endothelial cells. LINE-1 COBRA assay and immunohistochemistry using the 5-MC-specific antibody did not detect any changes in global DNA methylation in the endometriotic tissues. However, results from COBRA and bisulfite sequencing indicated that the LTR region of the syncytin-1 promoter is hypomethylated in endometriotic tissues, highlighting the significance of DNA demethylation in syncytin-1 gene activation. Analysis of DNA methyltransferase 3B (DNMT3B) mRNA levels revealed that DNMT3B3, an isoform carrying methyltransferase activity, is downregulated; whereas DNMT3B7, the isoform without enzymatic activity, is upregulated in the endometriotic tissues, pointing to positive and negative regulatory functions, respectively, of these isoforms on syncytin-1 methylation. These results have provided the first evidence supporting the involvement of epigenetic mechanisms for syncytin-1 upregulation in endometriotic tissues. Considering recent findings on the nonfusogenic activity of syncytin-1, its expression in endometriotic tissues suggests that this multifunctional protein may be implicated in the pathogenesis and/or progression of endometriosis.

Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology

“…Finally, two studies reported a high HERV-W expression in endometriotic tissues, even though no great differences were found with respect to control tissues [ 14 , 57 ]. This Syncytin-1 upregulation, dependent on the hypomethylation of its promoter, has been proposed to be involved in endometriotic lesion development [ 73 ].…”

Pregnancy Reprograms Large-Conductance Ca 2+ -Activated K + Channel in Uterine Arteries

“…61 Passive demethylation, occurring due to loss of maintenance methylation activity conferred by DNMTs, may also contribute to relieving gene repression. 62, 63 The potential involvement of passive demethylation in regulating KCNMB1 expression in pregnancy could not be excluded and merits further investigation.…”

Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells

“…The altered phenotype of endometriotic cells has a strong epigenetic component, and variation in DNMT is a putative mechanism affecting DNA methylation in diseased cells (29–32, 50–52). Here we demonstrated that EIUM and E-OSIS express all three DNMT isoforms, but that IVD treatment reduced DNMT3B only in healthy stromal cells.…”