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Cited by 64Endometriosis Research and TreatmentEpigenetics and DNA MethylationMicroRNA in disease regulation

Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis

Hsiao, Kuei-Yang, Wu, Meng-Hsing, Chang, Ning, Yang, Shang-Hsun, Wu, Chun-Wei, Sun, H. Sunny, Tsai, Shaw-Jenq·2015·Molecular Human Reproduction
DOI 10.1093/molehr/gav054
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Abstract

STUDY HYPOTHESIS: DNA methylation is regulated by hypoxia in endometriosis. STUDY FINDING: Hypoxia causes global hypomethylation through AU-rich element binding factor 1 (AUF1)/microRNA-148a (miR-148a)-mediated destabilization of DNA methyltransferase 1 (DNMT1) mRNA. WHAT IS KNOWN ALREADY: Eutopic endometrial and ectopic endometriotic stromal cells have the same genetic background, but differ in several cellular and molecular responses. Both hypoxia and DNA methylation regulate several genes involved in the development of endometriosis. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: This laboratory study included 15 patients of reproductive age with endometriosis or normal menstrual cycles. Paired endometrial and endometriotic tissues were collected for assaying the levels of DNMT1, 3a and 3b using quantitative RT-PCR, western blot and immunohistochemical (IHC) staining. Primary cultured endometrial stromal cells maintained in normoxia/hypoxia (1% O2) or treated with hypoxia-mimetic compounds were also assayed. The levels of DNA 5-methylcytosine were assayed by using IHC in clinical specimens and murine tissues, and by ELISA in cultured stromal cells. The 3'-untranslated region reporter assay was used to evaluate the effect of hypoxia, microRNAs (miRNAs) and human antigen R (HuR)/AUF1 on DNMT1 mRNA stability. RNA immunoprecipitation was used to assess the interaction of HuR/AUF1 and miR-148a/DNMT1 mRNA under hypoxia. Finally, a transplant-induced mouse model of endometriosis using 20 mice was used to elucidate the alteration of Dnmt1 levels and DNA methylation in the endometriotic tissues. MAIN RESULTS AND THE ROLE OF CHANCE: Levels of DNMT1 mRNA and protein and 5-methylcytosine were lower in the ectopic stromal cells (P < 0.05) than in the eutopic cells. Treatment with hypoxia and its mimetic compounds recapitulated the reduced levels of DNMT1 and 5-methylcytosine levels (P < 0.05 versus control). Hypoxia treatment destabilized DNMT1 mRNA through recruitment of miR-148a and AUF1. Mutations introduced to the miR-148a targeting site or AU-rich element (ARE) restored the hypoxia-suppressed DNMT1 3'-untranslated region (3'-UTR) reporter activity (P < 0.05 versus control). Levels of proteins of three hypermethylated genes in endometrial stroma cells, GATA6, HOXA3 and SLC16A5, were elevated after 72 h of hypoxia treatment (P < 0.05 versus control). Finally, a transplant-induced model of endometriosis demonstrated the down-regulation of DNMT1 and a decrease in 5-methylcytosine in the endometriotic tissues (P < 0.05, eutopic versus ectopic). LIMITATIONS, REASONS FOR CAUTION: Primary human cell cultures and a murine model were used in this study, and thus the results may not fully represent the situation in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to elucidate how microenvironmental hypoxia links to the epigenetic effects of DNA methylation in the endometriosis, and to delineate the molecular mechanism of hypoxia-coordinated AUF1/miR-148a interaction and recruitment to DNMT1 mRNA during the pathogenesis of endometriosis. The development of future therapeutics in endometriosis may aim at disrupting this specific interaction and eventually restore the epigenetic regulation. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by the National Science Council of Taiwan (NSC101-2320-B-006-030-MY3). The author declares that there are no conflicts of interest.

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Research works printed but not linked: 3

  1. Chang N, Yi J, Guo G, Liu X, Shang Y, Tong T, Cui Q, Zhan M, Gorospe M, Wang W. HuR uses AUF1 as a cofactor to promote p16INK4 mRNA decay. Mol Cell Biol 2010;30:3875 -3886.
  2. Kai K, Nasu K, Kawano Y, Aoyagi Y, Tsukamoto Y, Hijiya N, Abe W, Okamoto M, Moriyama M, Narahara H. Death receptor 6 is epigenetically silenced by histone deacetylation in endometriosis and promotes the pathogenesis of endometriosis. Am J Reprod Immunol 2013;70:485 -496.
  3. Wu MH, Lu CW, Chuang PC, Tsai SJ. Prostaglandin E2: the master of endometriosis? Exp Biol Med (Maywood) 2010;235:668 -677.

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Authors
Hsiao, K.-Y., Wu, M.-H., Chang, N., Yang, S.-H., Wu, C.-W., Sun, H. S., & Tsai, S.-J.
Affiliations
National Cheng Kung University (TW)
Corresponding author
  • Sun, H. Sunny
  • Tsai, Shaw-Jenq
ORCID
Venue
Molecular Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2015-10-03
Volume
21
Issue
12
Pages
894-904
ISSN
  • 1360-9947 (ISSN-L)
  • 1460-2407
DOI
10.1093/molehr/gav054
OpenAlex
W2189249738
Cited by
64
References
39
Citations by year
2026: 1 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 5
FWCI
6.46
Type
journal article
Language
en
Open access
closed
Locations
  • Molecular Human Reproduction (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Science Council of Taiwan (NSC101-2320-B-006-030-MY3)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
endometriosis, hypoxia, DNA methylation, DNMT1, AUF1, HuR, miR-148a, mRNA stability, AU-rich elements, 5-methylcytosine, endometrial stromal cells, hypoxia mimetics
MeSH terms
Heterogeneous Nuclear Ribonucleoprotein D0, Animals, Cell Line, Endometriosis, Female, Immunohistochemistry, RNA, Messenger, Blotting, Western, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Heterogeneous-Nuclear Ribonucleoprotein D, MicroRNAs, Epigenesis, Genetic, Immunoprecipitation, Mice

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