{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T07:35:07Z","timestamp":1774337707783,"version":"3.50.1"},"reference-count":37,"publisher":"The Endocrine Society","issue":"6","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["31971073"],"award-info":[{"award-number":["31971073"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004480","name":"Natural Science Foundation of Shanxi Province","doi-asserted-by":"crossref","award":["NSF201901D111328"],"award-info":[{"award-number":["NSF201901D111328"]}],"id":[{"id":"10.13039\/501100004480","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1210\/jendso\/bvad049","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T09:58:49Z","timestamp":1681811929000},"source":"Crossref","is-referenced-by-count":10,"title":["Regulation of HAND2 Expression by LncRNA <i>HAND2-AS1<\/i> in Ovarian Endometriosis Involving DNA Methylation"],"prefix":"10.1210","volume":"7","author":[{"given":"Lingli","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, Key Laboratory of Reproduction Engineer of Shanxi Health Committee , Changzhi, Shanxi 046000 , P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijing","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, Key Laboratory of Reproduction Engineer of Shanxi Health Committee , Changzhi, Shanxi 046000 , P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yining","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, Key Laboratory of Reproduction Engineer of Shanxi Health Committee , Changzhi, Shanxi 046000 , P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, Key Laboratory of Reproduction Engineer of Shanxi Health Committee , Changzhi, Shanxi 046000 , P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenxia","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Heping Hospital, Changzhi Medical College , Changzhi, Shanxi 046000 , P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6032-2632","authenticated-orcid":false,"given":"Indrani C","family":"Bagchi","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana-Champaign , Urbana, IL 61802 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0021-1559","authenticated-orcid":false,"given":"Congxiu","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, Key Laboratory of Reproduction Engineer of Shanxi Health Committee , Changzhi, Shanxi 046000 , P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8565-2336","authenticated-orcid":false,"given":"Quanxi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, Key Laboratory of Reproduction Engineer of Shanxi Health Committee , Changzhi, Shanxi 046000 , P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"issue":"1","key":"2024040910504147500_bvad049-B1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/1472-6874-14-123","article-title":"Impact of endometriosis on women's lives: a qualitative study","volume":"14","author":"Moradi","year":"2014","journal-title":"BMC Womens Health"},{"issue":"25","key":"2024040910504147500_bvad049-B2","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1056\/NEJMcp1000274","article-title":"Clinical practice. Endometriosis","volume":"362","author":"Giudice","year":"2010","journal-title":"N Engl J Med"},{"issue":"3","key":"2024040910504147500_bvad049-B3","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1056\/NEJMra0804690","article-title":"Endometriosis","volume":"360","author":"Bulun","year":"2009","journal-title":"N Engl J Med"},{"issue":"1-5","key":"2024040910504147500_bvad049-B4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0960-0760(02)00260-1","article-title":"Endometriosis: the pathophysiology as an estrogen-dependent disease","volume":"83","author":"Kitawaki","year":"2002","journal-title":"J Steroid Biochem Mol Biol"},{"issue":"4","key":"2024040910504147500_bvad049-B5","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1093\/humupd\/dmg030","article-title":"Progestogens for endometriosis: forward to the past","volume":"9","author":"Vercellini","year":"2003","journal-title":"Hum Reprod Update"},{"issue":"6","key":"2024040910504147500_bvad049-B6","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/aogs.13156","article-title":"Progesterone resistance in endometriosis: origins, consequences and interventions","volume":"96","author":"Patel","year":"2017","journal-title":"Acta Obstet Gynecol Scand"},{"issue":"1","key":"2024040910504147500_bvad049-B7","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1210\/er.2012-1043","article-title":"Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer","volume":"34","author":"Kim","year":"2013","journal-title":"Endocr Rev"},{"issue":"3","key":"2024040910504147500_bvad049-B8","doi-asserted-by":"crossref","first-page":"e1004158","DOI":"10.1371\/journal.pgen.1004158","article-title":"Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis","volume":"10","author":"Dyson","year":"2014","journal-title":"PLoS Genet"},{"issue":"6019","key":"2024040910504147500_bvad049-B9","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1126\/science.1197454","article-title":"The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2","volume":"331","author":"Li","year":"2011","journal-title":"Science"},{"issue":"28","key":"2024040910504147500_bvad049-B10","doi-asserted-by":"crossref","first-page":"9596","DOI":"10.1074\/jbc.RA120.012753","article-title":"The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells","volume":"295","author":"Murata","year":"2020","journal-title":"J Biol Chem"},{"issue":"6","key":"2024040910504147500_bvad049-B11","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1016\/j.fertnstert.2014.03.013","article-title":"Requirement of heart and neural crest derivatives-expressed transcript 2 during decidualization of human endometrial stromal cells in vitro","volume":"101","author":"Shindoh","year":"2014","journal-title":"Fertil Steril"},{"issue":"11","key":"2024040910504147500_bvad049-B12","doi-asserted-by":"crossref","first-page":"e1001551","DOI":"10.1371\/journal.pmed.1001551","article-title":"Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development","volume":"10","author":"Jones","year":"2013","journal-title":"PLoS Med"},{"issue":"1","key":"2024040910504147500_bvad049-B13","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s13148-019-0765-3","article-title":"Combined genetic mutations and DNA-methylated genes as biomarkers for endometrial cancer detection from cervical scrapings","volume":"11","author":"Liew","year":"2019","journal-title":"Clin Epigenetics"},{"issue":"1","key":"2024040910504147500_bvad049-B14","doi-asserted-by":"crossref","first-page":"e0170859","DOI":"10.1371\/journal.pone.0170859","article-title":"Epigenetic alterations affecting transcription factors and signaling pathways in stromal cells of endometriosis","volume":"12","author":"Yotova","year":"2017","journal-title":"PLoS One"},{"issue":"2","key":"2024040910504147500_bvad049-B15","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41580-020-00315-9","article-title":"Gene regulation by long non-coding RNAs and its biological functions","volume":"22","author":"Statello","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"3","key":"2024040910504147500_bvad049-B16","first-page":"3424","article-title":"The role of lncRNAs in the development of endometrial carcinoma","volume":"16","author":"Li","year":"2018","journal-title":"Oncol Lett"},{"key":"2024040910504147500_bvad049-B17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.canlet.2017.10.028","article-title":"Long non-coding RNA HAND2-AS1 inhibits invasion and metastasis in endometrioid endometrial carcinoma through inactivating neuromedin U","volume":"413","author":"Yang","year":"2018","journal-title":"Cancer Lett"},{"issue":"1","key":"2024040910504147500_bvad049-B18","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1471-2199-10-28","article-title":"Co-regulated expression of HAND2 and DEIN by a bidirectional promoter with asymmetrical activity in neuroblastoma","volume":"10","author":"Voth","year":"2009","journal-title":"BMC Mol Biol"},{"issue":"7629","key":"2024040910504147500_bvad049-B19","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature20128","article-title":"Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development","volume":"539","author":"Anderson","year":"2016","journal-title":"Nature"},{"issue":"5","key":"2024040910504147500_bvad049-B20","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1210\/en.2017-03000","article-title":"Bisphenol A and phthalates modulate peritoneal macrophage function in female mice involving SYMD2-H3K36 dimethylation","volume":"159","author":"Li","year":"2018","journal-title":"Endocrinology"},{"issue":"37","key":"2024040910504147500_bvad049-B21","doi-asserted-by":"crossref","first-page":"22423","DOI":"10.1074\/jbc.M115.642710","article-title":"Transcriptional activation of human CDCA8 gene regulated by transcription factor NF-Y in embryonic stem cells and cancer cells","volume":"290","author":"Dai","year":"2015","journal-title":"J Biol Chem"},{"issue":"10","key":"2024040910504147500_bvad049-B22","doi-asserted-by":"crossref","first-page":"e0165347","DOI":"10.1371\/journal.pone.0165347","article-title":"Progesterone alleviates endometriosis via inhibition of uterine cell proliferation, inflammation and angiogenesis in an immunocompetent mouse model","volume":"11","author":"Li","year":"2016","journal-title":"PLoS One"},{"issue":"1","key":"2024040910504147500_bvad049-B23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1055\/s-2004-823026","article-title":"Aromatase and endometriosis","volume":"22","author":"Bulun","year":"2004","journal-title":"Semin Reprod Med"},{"issue":"1","key":"2024040910504147500_bvad049-B24","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13578-016-0109-3","article-title":"Long noncoding RNAs in DNA methylation: new players stepping into the old game","volume":"6","author":"Zhao","year":"2016","journal-title":"Cell Biosci"},{"issue":"35","key":"2024040910504147500_bvad049-B25","doi-asserted-by":"crossref","first-page":"5483","DOI":"10.1038\/sj.onc.1205699","article-title":"5-Azacytidine And 5-aza-2\u2032-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy","volume":"21","author":"Christman","year":"2002","journal-title":"Oncogene"},{"issue":"1","key":"2024040910504147500_bvad049-B26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1177\/0022034510378683","article-title":"Epigenetic mechanisms in inflammation","volume":"90","author":"Bayarsaihan","year":"2011","journal-title":"J Dent Res"},{"issue":"1","key":"2024040910504147500_bvad049-B27","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.fertnstert.2006.05.077","article-title":"Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis","volume":"87","author":"Wu","year":"2007","journal-title":"Fertil Steril"},{"key":"2024040910504147500_bvad049-B28","doi-asserted-by":"crossref","first-page":"111317","DOI":"10.1016\/j.biopha.2021.111317","article-title":"HAND2-AS1: A functional cancer-related long non-coding RNA","volume":"137","author":"Gu","year":"2021","journal-title":"Biomed Pharmacother"},{"issue":"5","key":"2024040910504147500_bvad049-B29","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.devcel.2019.07.013","article-title":"The lncRNA locus handsdown regulates cardiac gene programs and is essential for early mouse development","volume":"50","author":"Ritter","year":"2019","journal-title":"Dev Cell"},{"issue":"3","key":"2024040910504147500_bvad049-B30","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1530\/REP-19-0401","article-title":"Progesterone-induced RNA Hand2os1 regulates decidualization in mice uteri","volume":"159","author":"Jia","year":"2020","journal-title":"Reproduction"},{"issue":"40","key":"2024040910504147500_bvad049-B31","doi-asserted-by":"crossref","first-page":"34788","DOI":"10.1074\/jbc.M111.275750","article-title":"Single-stranded noncoding RNAs mediate local epigenetic alterations at gene promoters in rat cell lines","volume":"286","author":"Tomikawa","year":"2011","journal-title":"J Biol Chem"},{"issue":"3","key":"2024040910504147500_bvad049-B32","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/cr.2015.21","article-title":"LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration","volume":"25","author":"Wang","year":"2015","journal-title":"Cell Res"},{"issue":"20","key":"2024040910504147500_bvad049-B33","doi-asserted-by":"crossref","first-page":"32821","DOI":"10.18632\/oncotarget.15826","article-title":"Identification of DBCCR1 as a suppressor in the development of lung cancer that is associated with increased DNA methyltransferase 1","volume":"8","author":"Zhou","year":"2017","journal-title":"Oncotarget"},{"issue":"18","key":"2024040910504147500_bvad049-B34","doi-asserted-by":"crossref","first-page":"5785","DOI":"10.1073\/pnas.1421197112","article-title":"Head-to-head antisense transcription and R-loop formation promotes transcriptional activation","volume":"112","author":"Boque-Sastre","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024040910504147500_bvad049-B35","first-page":"1","article-title":"HAND2-AS1 Works as a ceRNA of miR-3118 to suppress proliferation and migration in breast cancer by upregulating PHLPP2","volume":"2020","author":"Dong","year":"2020","journal-title":"Biomed Res Int"},{"key":"2024040910504147500_bvad049-B36","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.2147\/OTT.S233256","article-title":"Long non-coding RNA HAND2-AS1 inhibits growth and migration of gastric cancer cells through regulating the miR-590-3p\/KCNT2 axis","volume":"13","author":"Yu","year":"2020","journal-title":"Onco Targets Ther"},{"issue":"5","key":"2024040910504147500_bvad049-B37","first-page":"2103","article-title":"LncRNA HAND2-AS1 inhibits proliferation and promotes apoptosis of chronic myeloid leukemia cells by sponging with micRNA-1275","volume":"23","author":"Yang","year":"2019","journal-title":"Eur Rev Med Pharmacol Sci"}],"container-title":["Journal of the Endocrine Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jes\/advance-article-pdf\/doi\/10.1210\/jendso\/bvad049\/50007562\/bvad049.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jes\/article-pdf\/7\/6\/bvad049\/57188818\/bvad049.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jes\/article-pdf\/7\/6\/bvad049\/57188818\/bvad049.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,9]],"date-time":"2024-04-09T11:32:23Z","timestamp":1712662343000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jes\/article\/doi\/10.1210\/jendso\/bvad049\/7127468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,18]]},"references-count":37,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,5,5]]}},"URL":"https:\/\/doi.org\/10.1210\/jendso\/bvad049","relation":{},"ISSN":["2472-1972"],"issn-type":[{"value":"2472-1972","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6]]},"published":{"date-parts":[[2023,4,18]]},"article-number":"bvad049"}}