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Decreased DNA Methylations at the Progesterone Receptor Promoter A Induce Functional Progesterone Withdrawal in Human Parturition

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Abstract

The functional interaction of progesterone receptor (PR) isoforms PRA and PRB regulates myometrial transition from the resting state to excitation–contraction to initiate parturition. However, the regulatory mechanisms responsible for maintenance and functional alteration of the PRA and PRB expression levels during human pregnancy and term labor, respectively, remain unknown. Therefore, this study was designed to investigate whether and how epigenetic DNA modifications, specifically methylations, at the PRs’ promoter regions contribute to the differential expression of PRA and PRB in laboring term myometrium of humans. Comparative analysis of PRA and PRB messenger RNA (mRNA) expression levels and accompanying changes in their promoters’ methylation status was carried out using human myometrial samples from women undergoing singleton, term deliveries by cesarean section, either in the absence of labor (designated as NIL for not-in-labor) or in active labor (designated as IL for in labor). The PRA gene expression was shown to be elevated significantly during labor, while PRB gene expression was unaltered, and this differential expression was accompanied by decreased DNA methylation at the PRA promoter and not at the PRB promoter. In addition, labor-related decreased mRNA expression of the DNA methyltransferase (DNMT) family members DNMT1 and DNMT3a was found, however whether the increased expression of DNMTs directly supports the functional withdrawal of progesterone needs further investigation. Collectively, these data indicate that DNA methylation might represent an important epigenetic mechanism of labor-related differential expression of PRs, thereby mediating the biological process of functional PR withdrawal at term for parturition.

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References

  1. Tita AT, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol. 2009;200(3): 219–224.

    Article  CAS  Google Scholar 

  2. Mesiano S, Welsh TN. Steroid hormone control of myometrial contractility and parturition. Semin Cell Dev Biol. 2007;18(3): 321–331.

    Article  CAS  Google Scholar 

  3. Zakar T, Hertelendy F. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol. 2007;196(4):289–296.

    Article  CAS  Google Scholar 

  4. Goldman S, Shalev E. Progesterone receptor profile in the decidua and fetal membrane. Front Biosci. 2007;12:634–648.

    Article  CAS  Google Scholar 

  5. Mesiano S. Myometrial progesterone responsiveness. Semin Reprod Med. 2007;25(1):5–13.

    Article  CAS  Google Scholar 

  6. Pieber D, Allport VC, Hills F, Johnson M, Bennett PR. Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol Hum Reprod. 2001;7(9):875–879.

    Article  CAS  Google Scholar 

  7. Merlino AA, Welsh TN, Tan H, et al. Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A. J Clin Endocrinol Metab. 2007;92(5):1927–1933.

    Article  CAS  Google Scholar 

  8. Mesiano S, Wang Y, Norwitz ER. Progesterone receptors in the human pregnancy uterus: do they hold the key to birth timing? Reprod Sci. 2011;18(1):6–19.

    Article  CAS  Google Scholar 

  9. Mesiano S, Chan EC, Fitter JT, Kwek K, Yeo G, Smith R. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor a expression in the myometrium. J Clin Endocrinol Metab. 2002;87(6):2924–2930.

    Article  CAS  Google Scholar 

  10. Rountree MR, Bachman KE, Herman JG, Baylin SB. DNA methylation, chromatin inheritance, and cancer. Oncogene. 2001;20(24):3156–3165.

    Article  CAS  Google Scholar 

  11. Jeltsch A.Beyond Watson and Crick: DNA methylation and molecular enzymology of DNA methyltransferases. Chembio-chem. 2002;3(4):274–293.

    Article  CAS  Google Scholar 

  12. Wajed SA, Laird PW, DeMeester TR. DNA methylation: an alternative pathway to cancer. Ann Surg. 2001;234(1):10–20.

    Article  CAS  Google Scholar 

  13. Sasaki M, Tanaka Y, Perinchery G, et al. Methylation and inactivation of estrogen, progesterone, and androgen receptors in prostate cancer. J Natl Cancer Inst. 2002;94(5):384–390.

    Article  CAS  Google Scholar 

  14. Yang X, Yan L, Davidson NE. DNA methylation in breast cancer. Endocr Relat Cancer. 2001;8(2):115–127.

    Article  CAS  Google Scholar 

  15. Sasaki M, Oh BR, Dharia A, Fujimoto S, Dahiya R. Inactivation of the human androgen receptor gene is associated with CpG hypermethylation in uterine endometrial cancer. Mol Carcinog. 2000;29(2):59–66.

    Article  CAS  Google Scholar 

  16. Sasaki M, Dharia A, Oh BR, Tanaka Y, Fujimoto S, Dahiya R. Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer. Cancer Res. 2001; 61(1):97–102.

    CAS  PubMed  Google Scholar 

  17. Xiong Y, Dowdy SC, Gonzalez Bosquet J, et al. Epigenetic-mediated upregulation of progesterone receptor B gene in endometrial cancer cell lines. Gynecol Oncol. 2005;99(1):135–141.

    Article  CAS  Google Scholar 

  18. Chai SY, Smith R, Zakar T, Mitchell C, Madsen G. Term myometrium is characterized by increased activating epigenetic modifications at the progesterone receptor-A promoter. Mol Hum Reprod. 2012;18(8):401–409.

    Article  CAS  Google Scholar 

  19. Tung L, Mohamed MK, Hoeffler JP, Takimoto GS, Horwitz KB. Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors. Mol Endocrinol. 1993;7(10):1256–1265.

    CAS  PubMed  Google Scholar 

  20. Jin B, Robertson KD. DNA methyltransferases, DNA damage repair, and cancer. Adv Exp Med Biol. 2013;754:3–29.

    Article  CAS  Google Scholar 

  21. Kar S, Deb M, Sengupta D, et al. An insight into the various regulatory mechanisms modulating human DNA methyltransferase 1 stability and function. Epigenetics. 2012;7(9):994–1007.

    Article  CAS  Google Scholar 

  22. Condon JC, Jeyasuria P, Faust JM, Wilson JW, Mendelson CR. A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition. Proc Natl Acad Sci U S A. 2003;100(16):9518–9523.

    Article  CAS  Google Scholar 

  23. Allport VC, Pieber D, Slater DM, Newton R, White JO, Bennett PR. Human labour is associated with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expression and is involved with the ‘functional progesterone withdrawal’. Mol Hum Reprod. 2001;7(6):581–586.

    Article  CAS  Google Scholar 

  24. Sheehan PM, Rice GE, Moses EK, Brennecke SP. 5 Beta-dihydroprogesterone and steroid 5 beta-reductase decrease in association with human parturition at term. Mol Hum Reprod. 2005;11(7):495–501.

    Article  CAS  Google Scholar 

  25. Chalbos D, Galtier F. Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription. J Biol Chem. 1994;269(37):23007–23012.

    CAS  PubMed  Google Scholar 

  26. McDonnell DP, Shahbaz MM, Vegeto E, Goldman ME. The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity. J Steroid Biochem Mol Biol. 1994;48(5–6):425–432.

    Article  CAS  Google Scholar 

  27. Wen DX, Xu YF, Mais DE, Goldman ME, McDonnell DP. The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol. 1994;14(12):8356–8364.

    Article  CAS  Google Scholar 

  28. Giangrande PH, McDonnell DP. The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. Recent Prog Horm Res. 1999;54:291–313.

    CAS  PubMed  Google Scholar 

  29. Scarpin KM, Graham JD, Mote PA, Clarke CL. Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl Recept Signal. 2009;7:e009.

    Article  Google Scholar 

  30. Haluska GJ, Wells TR, Hirst JJ, Brenner RM, Sadowsky DW, Novy MJ. Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membranes from rhesus macaques: evidence for functional progesterone withdrawal at parturition. J Soc Gynecol Investig. 2002;9(3):125–136.

    CAS  PubMed  Google Scholar 

  31. Mc Cormack O, Chung WY, Fitzpatrick P, et al. Progesterone receptor B (PRB) promoter hypermethylation in sporadic breast cancer: progesterone receptor B hypermethylation in breast cancer. Breast Cancer Res Treat. 2008;111(1):45–53.

    Article  CAS  Google Scholar 

  32. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3(9): 662–673.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Southwestern Hospital, Third Military Medical University, Chongqing, 400038, PR China

    Xia Li MS, Cheng Chen MD, Hui Luo MD & Qing Chang MD

  2. van Velkinburgh Initiative for Collaboratory BioMedical Research, Santa Fe, NM, USA

    Jennifer C. van Velkinburgh PhD

  3. Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, PR China

    Bing Ni PhD

Authors
  1. Xia Li MS
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  2. Cheng Chen MD
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  3. Hui Luo MD
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  4. Jennifer C. van Velkinburgh PhD
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  5. Bing Ni PhD
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  6. Qing Chang MD
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Correspondence to Bing Ni PhD or Qing Chang MD.

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Li, X., Chen, C., Luo, H. et al. Decreased DNA Methylations at the Progesterone Receptor Promoter A Induce Functional Progesterone Withdrawal in Human Parturition. Reprod. Sci. 21, 898–905 (2014). https://doi.org/10.1177/1933719113518982

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