GRIK1-AS1 deficiency accelerates endometriosis progression by boosting DNMT1-dependent SFRP1 promoter methylation in endometrial stromal cells

Endometriosis, a gynecological disease that affects up to 10% of women, is a major cause of pain and infertility. Deregulation of the epigenome is accountable for the onset and progression of endometriosis, although its exact mechanism is unknown. The

Our study is a proof-of-concept demonstration for GRIKI-AS1-associated endometriosis pathogenesis and highlights a potential intervention target.

Endometriosis datasets were screened to identify GRIKI-AS1 as dramatically declining in endometriosis. Gain or loss of function endometrial stromal cell (ESC) models were established. The anti-proliferation phenotype was investigated using in vitro and in vivo experiments. Epigenetic regulatory network analyses were conducted to suggest the intrinsic molecular mechanism.

With bioinformatic and clinical data, we observed that GRIK1-AS1 and SFRP1 were expressed at low levels in endometriosis. Overexpressed GRIK1-AS1 inhibited ESC proliferation, while SFRP1 knockdown rescued the antiproliferative ability of GRIK1-AS1. Specifically, methylation-dependent expression inhibition of SFRP1 was revealed in ESCs. Mechanistically, GRIK1-AS1 hampers the occupancy of DNMT1 in SRFP1 promoter, leading to hypomethylation of SFRP1 and upregulated SFRP1 expression, thereby potentially suppressing Wnt signaling and its adverse proliferative effect. Therapeutically, lentivirus-mediated upregulation of GRIK1-AS1 inhibited endometriosis disease progression in vivo. Conclusions: Our study is a proof-of-concept demonstration for GRIKI-AS1-associated endometriosis pathogenesis and highlights a potential intervention target.