Promoter Methylation Regulates Estrogen Receptor 2 in Human Endometrium and Endometriosis

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 recepto...

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Vydáno v:Biology of reproduction Ročník 77; číslo 4; s. 681 - 687
Hlavní autoři: Xue, Qing, Lin, Zhihong, Cheng, You-Hong, Huang, Chiang-Ching, Marsh, Erica, Yin, Ping, Milad, Magdy P, Confino, Edmond, Reierstad, Scott, Innes, Joy, Bulun, Serdar E
Médium: Journal Article
Jazyk:angličtina
Vydáno: Madison, WI Society for the Study of Reproduction, Inc 01.10.2007
Society for the Study of Reproduction
Témata:
Adult
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Biological and medical sciences
Cells, Cultured
CpG Islands
DNA Methylation
Endometriosis - genetics
Endometrium - drug effects
Endometrium - metabolism
Estrogen Receptor alpha - genetics
Estrogen Receptor beta - genetics
Female
Female genital diseases
Gene Expression Regulation - genetics
Gynecology. Andrology. Obstetrics
Humans
Medical sciences
Non tumoral diseases
Promoter Regions, Genetic - drug effects
Receptors, Progesterone - genetics
RNA, Messenger - analysis
RNA, Messenger - metabolism
Stromal Cells - drug effects
Stromal Cells - metabolism
Human
Estrogen receptor
estradiol receptor
17β-Estradiol
Endometriosis
CpG island
ESR2
Female genital diseases
Promoter
Ovary
Uterus
DNA
Uterine diseases
DNA methylation
Methylation
Endometrium
Biological receptor
ISSN:0006-3363, 1529-7268
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Shrnutí: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.
Bibliografie:http://www.biolreprod.org/
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ISSN:0006-3363
1529-7268
DOI:10.1095/biolreprod.107.061804