Downregulation of lncPVT1 impairs endometrial receptivity through upregulating mannosyltransferases 12 (ALG12)/α1,6-high mannose biosynthesis

Endometrial receptivity establishment is a prerequisite for embryo implantation. Dysfunction of uterus is closely associated with the pregnancy-related disorders, including spontaneous miscarriage. Protein N-glycosylation is initiated by high mannose biosynthesis, which is involved in embryo implantation. Long non-coding RNA plasmacytoma variant transloation 1 (lncPVT1) exerts important roles in a wide range of physiological and pathological processes. However, the function and underlying molecular mechanisms of lncPVT1 and ALG12/high mannose in endometrial receptivity establishment remain poorly understood. Here, our results revealed that the levels of α1,6-high mannose and its key enzyme ALG12 were significantly elevated in the epithelium of decidualized endometrium from miscarriage patients, compared with normal early pregnant control. Enhanced α1,6-high mannose biosynthesis by ALG12 significantly inhibited the adhesion of trophoblastic cells to endometrial epithelial cells. Moreover, the level of lncPVT1 was decreased in specimens from miscarriage patients. Employing RNA pull down combined with proteomic analysis, we globally screened and identified the transcription factor Yin Yang 2 (YY2) as the binding factor of lncPVT1. YY2 is the specific transcription factor for ALG12. Decreased lncPVT1 reduces its binding to YY2, which in turn enables increased recruitment of YY2 to the ALG12 promoter, further promotes ALG12 expression and α1,6-high mannose biosynthesis, and hampers the establishment of endometrial receptivity. This study provides new insight into the endometrial receptivity and a target for the treatment of clinical miscarriage.