The DOI matches its Crossref record; 42 of the 43 references it cites were found in a registry or an index.
Promoter Methylation Regulates Estrogen Receptor 2 in Human Endometrium and Endometriosis1
Abstract
Steroid receptors in the stromal cells of endometrium and its disease counterpart tissue endometriosis play critical physiologic roles. We found that mRNA and protein levels of estrogen receptor 2 (ESR2) were strikingly higher, whereas levels of estrogen receptor 1 (ESR1), total progesterone receptor (PGR), and progesterone receptor B (PGR B) were significantly lower in endometriotic versus endometrial stromal cells. Because ESR2 displayed the most striking levels of differential expression between endometriotic and endometrial cells, and the mechanisms for this difference are unknown, we tested the hypothesis that alteration in DNA methylation is a mechanism responsible for severely increased ESR2 mRNA levels in endometriotic cells. We identified a CpG island occupying the promoter region (-197/+359) of the ESR2 gene. Bisulfite sequencing of this region showed significantly higher methylation in primary endometrial cells (n = 8 subjects) versus endometriotic cells (n = 8 subjects). The demethylating agent 5-aza-2'-deoxycytidine significantly increased ESR2 mRNA levels in endometrial cells. Mechanistically, we employed serial deletion mutants of the ESR2 promoter fused to the luciferase reporter gene and transiently transfected into both endometriotic and endometrial cells. We demonstrated that the critical region (-197/+372) that confers promoter activity also bears the CpG island, and the activity of the ESR2 promoter was strongly inactivated by in vitro methylation. Taken together, methylation of a CpG island at the ESR2 promoter region is a primary mechanism responsible for differential expression of ESR2 in endometriosis and endometrium. These findings may be applied to a number of areas ranging from diagnosis to the treatment of endometriosis.
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“In addition, ERβ is also hypermethylated and silenced in normal endometrial stromal cells [71].”
From The Pathogenesis of Adenomyosis vis-à-vis Endometriosis (2020) · cites this paper as [71]
In the citing paper
“Higher expression of estrogen receptor amplifies estrogenic effects and the proliferative capacity of endometrial cells.26,27”
From Altered genome-wide methylation in endometriosis (2014) · cites this paper as [27]
Citations
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Krege, J. H., Hodgin, J. B., Couse, J. F., Enmark, E., Warner, M. N., Mahler, J. F., Sar, M., Korach, K. S., Gustafsson, J.-Α., & Smithies, O. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15677 · Cited by 1,717
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Endometriosis: pathogenesis and treatment
Vercellini, P., Viganò, P., Somigliana, E., & Fedele, L. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.255 · Cited by 1,940
Bulun, S. E. (2009) · New England Journal of Medicine · doi:10.1056/nejmra0804690 · Cited by 1,772
Self-citationEndometriosis is a chronic systemic disease: Clinical challenges and novel innovations
Taylor, H. S., Kotlyar, A. M., & Flores, V. A. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00389-5 · Cited by 1,425
Bulun, S. E., Yilmaz, B. D., Sison, C., Miyazaki, K., Bernardi, L., Liu, S., Kohlmeier, A., Yin, P., Milad, M., & Wei, J. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00242 · Cited by 844
Self-citationProgesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer
Kim, J. J., Kurita, T., & Bulun, S. E. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1043 · Cited by 520
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Metadata
- Authors
- Xue, Q., Lin, Z., Cheng, Y.-H., Huang, C.-C., Marsh, E., Yin, P., Milad, M. P., Confino, E., Reierstad, S., Innes, J., & Bulun, S. E.
- Affiliations
- Northwestern University (US)
- Peking University (CN)
- Corresponding author
- Bulun, Serdar E.
- Venue
- Biology of Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-10-01
- Volume
- 77
- Issue
- 4
- Pages
- 681-687
- ISSN
- 0006-3363 (ISSN-L)
- 1529-7268
- OpenAlex
- W2164434026
- Cited by
- 346
- References
- 43
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 20 · 2023: 30 · 2022: 19 · 2021: 24 · 2020: 23 · 2019: 25 · 2018: 16 · 2017: 15 · 2016: 14 · 2015: 22 · 2014: 27 · 2013: 14 · 2012: 24
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biology of Reproduction (publishedVersion)
- PubMed (publishedVersion)
- BioOne Complete (BioOne) (submittedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD040093, U54-HD40093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- estrogen receptor 2, endometriosis, endometrium, DNA methylation, promoter methylation, CpG islands, endometrial stromal cells, estrogen receptor 1, progesterone receptor, gene expression regulation, decitabine, promoter deletion mutants
- MeSH terms
- Decitabine, Adult, Azacitidine, Cells, Cultured, Endometriosis, Endometrium, Female, Gene Expression Regulation, Humans, Promoter Regions, Genetic, Receptors, Progesterone, RNA, Messenger, Stromal Cells, CpG Islands, DNA Methylation, Estrogen Receptor alpha, Estrogen Receptor beta
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