Regulation of HAND2 Expression by LncRNA HAND2-AS1 in Ovarian Endometriosis Involving DNA Methylation

Lingli Liu, Huijing Dong, Yining Guan, Tingting Fan, Wenxia Sun, Indrani C. Bagchi, Congxiu Miao, Quanxi Li
Journal of the Endocrine Society · 2023 · vol. 7(6) , pp. bvad049 · doi:10.1210/jendso/bvad049 · PMID:37153110 · W4366279963
article OA: gold CC0 ⤵ 6 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This study found reduced HAND2 and HAND2-AS1 expression and increased HAND2 promoter methylation in ectopic endometrium, with HAND2-AS1 epigenetically regulating HAND2 expression through DNMT1.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This study examined HAND2 expression and investigated whether the lncRNA HAND2-AS1 regulates HAND2 through DNA methylation in ovarian endometriosis. Using immunohistochemistry, qRT-PCR, fluorescence in situ hybridization, and mechanistic assays in primary human endometrial stromal cells (including siRNA knockdown or HAND2-AS1 overexpression, decidualization induction, methylation analysis by EpiTect Methyl II, bisulfite sequencing validation, and RNA immunoprecipitation for DNMT1), the authors found HAND2 mRNA and nuclear protein levels were markedly reduced in ovarian ectopic endometrial lesions compared with secretory-phase normal endometrium, consistent with a link between HAND2 downregulation and endometriosis development. A key limitation is that the mechanistic results described are based on in vitro stromal-cell experiments and archived tissue analyses from specific sampling time points, without clear demonstration of causal HAND2-AS1→methylation→HAND2 effects in vivo. This paper is centrally about endometriosis — specifically, it tests HAND2 and its regulation by HAND2-AS1 and DNA methylation in ovarian endometriosis lesions versus normal endometrium.

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Abstract

Abstract HAND2 is a critical mediator of progesterone receptor signaling in endometrium. Silencing of HAND2 expression is associated with female infertility and endometrial cancers. We recently observed that lncRNA HAND2-AS1 and HAND2 are expressed coordinately in human endometrial stromal cells. To investigate involvement of HAND2-AS1 and HAND2 in pathogenesis of endometriosis, we employed immunohistochemistry, in situ hybridization, and quantitative real-time PCR to assess their expression in normal endometrium and the ectopic lesions obtained from patients with ovarian endometriosis. HAND2 promoter methylation was also monitored in these samples. Our results revealed that HAND2 and HAND2-AS1 expression levels were reduced but promoter methylation was enhanced significantly in ectopic endometrium when compared with the normal controls. Fluorescence in situ hybridization showed that HAND-AS1 is predominantly localized in the nuclei of endometrial stromal cells in contrast to the cytoplasmic distribution in epithelial cell compartment. To further investigate regulation of HAND2 expression by HAND2-AS1, HAND2-AS1 was silenced or overexpressed in human endometrial stromal cells. Our studies showed that expression levels of HAND2 and its direct target IL15 were attenuated markedly in HAND2-AS1 silenced cells but enhanced significantly in the overexpressed human endometrial stromal cells. Silencing of HAND2-AS1 also impaired endometrial stromal cell decidualization as indicated by downregulation of decidual biomarkers IGFBP1 and PRL. In addition, HAND2 promoter methylation was also enhanced upon HAND2-AS1 silencing. RNA immunoprecipitation studies further revealed that HAND2-AS1 is capable of binding to DNA methyltransferase DNMT1, indicating that HAND2-AS1 governs HAND2 expression epigenetically involving DNA methylation.

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endometriosisinfertility

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