Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells
Decidualizing signals reduce deoxyribonucleic acid methyltransferase 3B (DNMT3B) expression in eutopic endometrial stromal cells but not in endometriotic stromal cells. This affects DNMT3B chromatin occupancy across genes with aberrant DNA methylation in endometriosis.
Matthew T. Dyson, Ph.D., Toshiyuki Kakinuma, M.D., Mary Ellen Pavone, M.D., Diana Monsivais, Ph.D., Antonia Navarro, Ph.D., Saurabh S. Malpani, M.S., Masanori Ono, M.D., Serdar E. Bulun, M.D.
Volume 104, Issue 4, Pages 953-963
To define the expression and function of DNA methyltransferases (DNMTs) in response to decidualizing stimuli in endometriotic cells compared with healthy endometrial stroma.
University research center.
Premenopausal women with or without endometriosis.
Primary cultures of stromal cells from healthy endometrium (E-IUM) or endometriomas (E-OSIS) were subjected to in vitro decidualization (IVD) using 1 μM medroxyprogesterone acetate, 35 nM 17β-estradiol, and 0.05 mM 8-Br-cAMP.
Main Outcome Measure(s):
Expression of DNMT1, DNMT3A, and DNMT3B in E-IUM and E-OSIS were assessed by quantitative real-time polymerase chain reaction and immunoblotting. Recruitment of DNMT3B to the promoters of steroidogenic factor 1 (SF-1) and estrogen receptor α (ESR1) was examined by chromatin immunoprecipitation.
Treatment of IVD reduced DNMT3B messenger RNA (74%) and protein levels (81%) only in E-IUM; DNMT1 and DNMT3A were unchanged in both cell types. Significantly more DNMT3B bound to the SF-1 promoter in E-IUM compared with E-OSIS, and IVD treatment reduced binding in E-IUM to levels similar to those in E-OSIS. Enrichment of DNMT3B across 3 ESR1 promoters was reduced in E-IUM after IVD, although the more-distal promoter showed increased DNMT3B enrichment in E-OSIS after IVD.
The inability to downregulate DNMT3B expression in E-OSIS may contribute to an aberrant epigenetic fingerprint that misdirects gene expression in endometriosis and contributes to its altered response to steroid hormones.