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The Impact of Multiparity on Uterine Gene Expression and Decidualization in Mice

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Abstract

It has been well established that a previous pregnancy exhibits a beneficial effect on the subsequent pregnancy. However, the underlying mechanisms have not been defined. We hypothesized that multiparity may affect decidualization process during early pregnancy. To test this hypothesis, we analyzed global gene changes associated with multiparity in the mouse uterus using RNA-sequencing (RNA-seq). We identified a total of 131 differentially expressed genes (fold change > 2 and false discovery rate < 0.05), of which 58 were downregulated and 73 genes were upregulated in the second pregnancy (SP) compared to the first pregnancy. Functional clustering analysis showed that genes involved in stress response were significantly enriched. Most importantly, a significant portion of differentially expressed genes, 14 genes or 10.7%, overlapped with the gene list associated with decidualization. Quantitative reverse transcription (RT) polymerase chain reaction (qRT-PCR) analysis confirmed a decreased expression of 4 genes (Klk1, kallikrein 1; H2-Eb1, histocompatibility 2 class II antigen E beta; Mmp7, matrix metallopeptidase 7; Pdpn, podoplanin) and an increase in expression of 2 genes (Thy1, thymus cell antigen 1; Ptgs2, prostaglandin-endoperoxide synthase 2) in SP. Beyond protein-coding genes, we also identified a differentially expressed long noncoding RNA AI506816. Our data provide new insights into the molecular mechanisms underlying the beneficial effect of multiparity.

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References

  1. Trupin LS, Simon LP, Eskenazi B. Change in paternity: a risk factor for preeclampsia in multiparas. Epidemiology. 1996;7(3): 240–244.

    Article  CAS  PubMed  Google Scholar 

  2. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet. 2001;357(9249):53–56.

    Article  CAS  PubMed  Google Scholar 

  3. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005; 330(7491):565.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk factors for preeclampsia. JAMA. 1991;266(2):237–241.

    Article  CAS  PubMed  Google Scholar 

  5. Lie RT, Rasmussen S, Brunborg H, et al. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ. 1998;316(7141):1343–1347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Macgillivray I. Some observations on the incidence of preeclampsia. J Obstet Gynaecol Br Emp. 1958;65(4):536–539.

    Article  CAS  PubMed  Google Scholar 

  7. Eras JL, Saftlas AF, Triche E, et al. Abortion and its effect on risk of preeclampsia and transient hypertension. Epidemiology. 2000; 11(1):36–43.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang J, Zeisler J, Hatch MC, Berkowitz G. Epidemiology of pregnancy-induced hypertension. Epidemiol Rev. 1997; 19(2): 218–232.

    Article  CAS  PubMed  Google Scholar 

  9. Esplin MS, Fausett MB, Fraser A, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med. 2001;344(12):867–872.

    Article  CAS  PubMed  Google Scholar 

  10. Harlap S, Paltiel O, Deutsch L, et al. Paternal age and preeclampsia. Epidemiology. 2002;13(6):660–667.

    Article  PubMed  Google Scholar 

  11. Tan CY, Ho JF, Chong YS, et al. Paternal contribution of HLAG*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies. Mol Hum Reprod. 2008;14(5):317–324.

    Article  CAS  PubMed  Google Scholar 

  12. Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of preeclampsia. N Engl J Med. 2002;346(1):33–38.

    Article  PubMed  Google Scholar 

  13. Beaty TH, Skjaerven R, Breazeale DR, Liang KY. Analyzing sibship correlations in birth weight using large sibships from Norway. Genet Epidemiol. 1997;14(4):423–433.

    Article  CAS  PubMed  Google Scholar 

  14. Hinkle SN, Albert PS, Mendola P, et al. The association between parity and birthweight in a longitudinal consecutive pregnancy cohort. Paediatr Perinat Epidemiol. 2014;28(2):106–115.

    Article  PubMed  Google Scholar 

  15. Shah PS. Parity and low birth weight and preterm birth: a systematic review and meta-analyses. Acta Obstet Gynecol Scand. 2010;89(7):862–875.

    Article  PubMed  Google Scholar 

  16. Chaouat G, Kolb JP, Kiger N, Stanislawski M, Wegmann TG. Immunologic consequences of vaccination against abortion in mice. J Immunol. 1985;134(3):1594–1598.

    CAS  PubMed  Google Scholar 

  17. Kiger N, Chaouat G, Kolb JP, Wegmann TG, Guenet JL. Immunogenetic studies of spontaneous abortion in mice. Preimmunization of females with allogeneic cells. J Immunol. 1985;134(5): 2966–2970.

    CAS  PubMed  Google Scholar 

  18. Brown LY, Bonney EA, Raj RS, Nielsen B, Brown S. Generalized disturbance of DNA methylation in the uterine decidua in the CBA/J x DBA/2 mouse model of pregnancy failure. Biol Reprod. 2013;89(5):120.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Ghulmiyyah LM, Tamayo E, Clark SM, et al. Effect of a previous pregnancy on vascular function in endothelial nitric oxide synthase 3 knockout mice. Am J Obstet Gynecol. 2007;197(3): 279 e271–e275.

    Article  CAS  Google Scholar 

  20. Zhang S, Lin H, Kong S, et al. Physiological and molecular determinants of embryo implantation. Mol Aspects Med. 2013;34(5): 939–980.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Dey SK, Lim H, Das SK, et al. Molecular cues to implantation. Endocr Rev. 2004;25(3):341–373.

    Article  CAS  PubMed  Google Scholar 

  22. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7(3):185–199.

    Article  CAS  PubMed  Google Scholar 

  23. Blois SM, Klapp BF, Barrientos G. Decidualization and angiogenesis in early pregnancy: unravelling the functions of DC and NK cells. J Reprod Immunol. 2011;88(2):86–92.

    Article  CAS  PubMed  Google Scholar 

  24. Barrientos G, Freitag N, Tirado-Gonzalez I, et al. Involvement of galectin-1 in reproduction: past, present and future. Hum Reprod Update. 2014;20(2):175–193.

    Article  CAS  PubMed  Google Scholar 

  25. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35(6):851–905.

    Article  CAS  PubMed  Google Scholar 

  26. Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009;25(9): 1105–1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Trapnell C, Williams BA, Pertea G, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28(5):511–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhu Y, King BL, Parvizi B, et al. Integrating computationally assembled mouse transcript sequences with the Mouse Genome Informatics (MGI) database. Genome Biol. 2003;4(2):R16.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5(7):621–628.

    Article  CAS  PubMed  Google Scholar 

  30. Brown GR, Hem V, Katz KS, et al. Gene: a gene-centered information resource at NCBI. Nucleic Acids Res. 2015;43(database issue):D36–D42.

    Article  CAS  PubMed  Google Scholar 

  31. Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10(1):57–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ruocco MG, Chaouat G, Florez L, Bensussan A, Klatzmann D. Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions. Front Immunol. 2014;5:389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Chen T, Darrasse-Jeze G, Bergot AS, et al. Self-specific memory regulatory T cells protect embryos at implantation in mice. J Immunol. 2013;191(5):2273–2281.

    Article  CAS  PubMed  Google Scholar 

  34. Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature. 2012; 490(7418):102–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dos Santos CO, Dolzhenko E, Hodges E, Smith AD, Hannon GJ. An epigenetic memory of pregnancy in the mouse mammary gland. Cell Rep. 2015;11(7): 1102–1109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bernstein L, Depue RH, Ross RK, et al. Higher maternal levels of free estradiol in first compared to second pregnancy: early gestational differences. J Natl Cancer Inst. 1986;76(6): 1035–1039.

    CAS  PubMed  Google Scholar 

  37. Bridges RS, Byrnes EM. Reproductive experience reduces circulating 17beta-estradiol and prolactin levels during proestrus and alters estrogen sensitivity in female rats. Endocrinology. 2006; 147(5):2575–2582.

    Article  CAS  PubMed  Google Scholar 

  38. Liu JL, Wang TS. Systematic analysis of the molecular mechanism underlying decidualization using a text mining approach. PLoS One. 2015;10(7):e0134585.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Chan CS, Harvey MB, Clements JA. Temporal and tissue-specific expression of kallikrein (Klk) genes and identification of a novel Klk messenger ribonucleic acid transcript during early development in the mouse. Biol Reprod. 1999;61(3):621–628.

    Article  CAS  PubMed  Google Scholar 

  40. Rajapakse S, Yamano N, Ogiwara K, et al. Estrogen-dependent expression of the tissue kallikrein gene (Klk1) in the mouse uterus and its implications for endometrial tissue growth. Mol Reprod Dev. 2007;74(8):1053–1063.

    Article  CAS  PubMed  Google Scholar 

  41. Weiss A, Goldman S, Shalev E. The matrix metalloproteinases (MMPS) in the decidua and fetal membranes. Front Biosci. 2007;12:649–659.

    Article  CAS  PubMed  Google Scholar 

  42. Rechtman MP, Zhang J, Salamonsen LA. Effect of inhibition of matrix metalloproteinases on endometrial decidualization and implantation in mated rats. J Reprod Fertil. 1999;117(1): 169–177.

    Article  CAS  PubMed  Google Scholar 

  43. Meuleman T, Lashley LE, Dekkers OM, et al. HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis. Hum Immunol. 2015;76(5):362–373.

    Article  CAS  PubMed  Google Scholar 

  44. Volchek M, Girling JE, Lash GE, et al. Lymphatics in the human endometrium disappear during decidualization. Hum Reprod. 2010;25(10):2455–2464.

    Article  PubMed  Google Scholar 

  45. Schuring AN, Schulte N, Kelsch R, et al. Characterization of endometrial mesenchymal stem-like cells obtained by endometrial biopsy during routine diagnostics. Fertil Steril. 2011;95(1): 423–426.

    Article  PubMed  Google Scholar 

  46. Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod. 2009;80(6): 1136–1145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chakraborty I, Das SK, Wang J, Dey SK. Developmental expression of the cyclo-oxygenase-1 and cyclo-oxygenase-2 genes in the peri-implantation mouse uterus and their differential regulation by the blastocyst and ovarian steroids. J Mol Endocrinol. 1996; 16(2):107–122.

    Article  CAS  PubMed  Google Scholar 

  48. Lim H, Paria BC, Das SK, et al. Multiple female reproductive failures in cyclooxygenase 2–deficient mice. Cell. 1997;91(2): 197–208.

    Article  CAS  PubMed  Google Scholar 

  49. Wang H, Ma WG, Tejada L, et al. Rescue of female infertility from the loss of cyclooxygenase-2 by compensatory upregulation of cyclooxygenase-1 is a function of genetic makeup. J Biol Chem. 2004;279(11): 10649–10658.

    Article  CAS  PubMed  Google Scholar 

  50. Wu L, Candille SI, Choi Y, et al. Variation and genetic control of protein abundance in humans. Nature. 2013;499(7456):79–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15(1):7–21.

    Article  CAS  PubMed  Google Scholar 

  52. Wang Y, Xu Z, Jiang J, et al. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell. 2013;25(1):69–80.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Ji-Long Liu PhD.

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Liu, JL., Zuo, RJ., Peng, Y. et al. The Impact of Multiparity on Uterine Gene Expression and Decidualization in Mice. Reprod. Sci. 23, 687–694 (2016). https://doi.org/10.1177/1933719115612131

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