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Genome-wide DNA methylation profiling in ectopic and eutopic of endometrial tissues

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Endometriosis is a gynecological disease that causes the uterine lining to appear in other organs outside the uterus. As DNA methylation has an important role in this disorder, its profiling can reveal new information to improve the diagnosis and treatment of endometriosis patients.

Methods

We conducted a genome-wide methylation profiling of ectopic and eutopic endometrial tissues from women with and without endometriosis using Infinium Human Methylation 450K BeadChip arrays. DNA methylation samples were collected from nine ectopic and nine eutopic endometrial tissues of endometriosis and six endometrial tissues of healthy controls.

Results

Correlation heatmaps and the principal component analysis divided the samples into two clusters, one consisting of all ectopic samples and the other consisting of both eutopic and control samples unexpectedly without segregation between them. The assay identified a group of methylated genes that were overrepresented in biological processes, including abnormality in signaling, development, and adhesion of cells. Pathway analysis revealed disruption in HTLV infection pathways, PI3K-Akt, oxytocin, and relaxin signaling. Moreover, we found eutopic lesions are strongly associated with autoimmune disease.

Conclusions

Our results confirmed the role of DNA methylation alternations in endometriosis development and pathogenesis. Our finding suggests aberrant DNA methylation can activate several signaling pathways including PI3k-AKT signaling, relaxin, and oxytocin which are associated with the pathogenesis of endometriosis.

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References

  1. Barton-Smith P, Ballard K, Kent A. Endometriosis: a general review and rationale for surgical therapy. Reviews in Gynaecological and Perinatal Practice. 2006;6(3–4):168–76.

    Article  Google Scholar 

  2. Aznaurova YB, Zhumataev MB, Roberts TK, Aliper AM, Zhavoronkov AA. Molecular aspects of development and regulation of endometriosis. Reproductive biology and endocrinology: RB&E. 2014;12:50.

    Article  Google Scholar 

  3. Baranov VS, Ivaschenko TE, Liehr T, Yarmolinskaya MI. Systems genetics view of endometriosis: a common complex disorder. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2015;185:59–65.

    Article  Google Scholar 

  4. Hadfield R, Mardon H, Barlow D, Kennedy S. Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK. Hum Reprod. 1996;11(4):878–80.

    Article  CAS  Google Scholar 

  5. Oral E, Arici A. Pathogenesis of endometriosis. Obstet Gynecol Clin N Am. 1997;24(2):219–33.

    Article  CAS  Google Scholar 

  6. Simpson JL, Elias S, Malinak LR, Buttram VC. Heritable aspects of endometriosis: I. Genetic studies. Am J Obstet Gynecol. 1980;137(3):327–31.

    Article  CAS  Google Scholar 

  7. Izawa M, Taniguchi F, Harada T. Epigenetics in endometriosis. In: Endometriosis. Berlin: Springer; 2014. p. 107–23.

    Google Scholar 

  8. Guo S-W. Epigenetics of endometriosis. Mol Hum Reprod. 2009;15(10):587–607.

    Article  CAS  Google Scholar 

  9. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011;25(10):1010–22.

    Article  CAS  Google Scholar 

  10. Brenet F, Moh M, Funk P, Feierstein E, Viale AJ, Socci ND, et al. DNA methylation of the first exon is tightly linked to transcriptional silencing. PLoS One. 2011;6(1):e14524.

    Article  CAS  Google Scholar 

  11. Xue Q, Lin Z, Cheng Y-H, Huang C-C, Marsh E, Yin P, et al. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod. 2007;77(4):681–7.

    Article  CAS  Google Scholar 

  12. Xue Q, Lin Z, Yin P, Milad MP, Cheng Y-H, Confino E, et al. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis. J Clin Endocrinol Metab. 2007;92(8):3261–7.

    Article  CAS  Google Scholar 

  13. Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo S-W. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol. 2005;193(2):371–80.

    Article  CAS  Google Scholar 

  14. Izawa M, Taniguchi F, Uegaki T, Takai E, Iwabe T, Terakawa N, et al. Demethylation of a nonpromoter cytosine-phosphate-guanine island in the aromatase gene may cause the aberrant up-regulation in endometriotic tissues. Fertil Steril. 2011;95(1):33–9.

    Article  CAS  Google Scholar 

  15. Eyster KM, Boles AL, Brannian JD, Hansen KAJF. DNA microarray analysis of gene expression markers of endometriosis. Ferti Steril. 2002;77(1):38–42.

    Article  Google Scholar 

  16. Arimoto T, Katagiri T, Oda K, Tsunoda T, Yasugi T, Osuga Y, et al. Genome-wide cDNA microarray analysis of gene-expression profiles involved in ovarian endometriosis. Int J Oncol. 2003;22(3):551–60.

    CAS  PubMed  Google Scholar 

  17. Nasu K, Kawano Y, Tsukamoto Y, Takano M, Takai N, Li H, et al. Aberrant DNA methylation status of endometriosis: epigenetics as the pathogenesis, biomarker and therapeutic target. J Obstet Gynaecol Res. 2011;37(7):683–95.

    Article  CAS  Google Scholar 

  18. Borghese B, Barbaux S, Mondon F, Santulli P, Pierre G, Vinci G, et al. Research resource: genome-wide profiling of methylated promoters in endometriosis reveals a subtelomeric location of hypermethylation. Mol Endocrinol. 2010;24(9):1872–85.

    Article  CAS  Google Scholar 

  19. Naqvi H, Ilagan Y, Krikun G, Taylor HS. Altered genome-wide methylation in endometriosis. Reprod Sci. 2014;21(10):1237–43.

    Article  CAS  Google Scholar 

  20. Yamagata Y, Nishino K, Takaki E, Sato S, Maekawa R, Nakai A, et al. Genome-wide DNA methylation profiling in cultured eutopic and ectopic endometrial stromal cells. PLoS One. 2014;9(1):e83612.

    Article  Google Scholar 

  21. Sandoval J, Heyn H, Moran S, Serra-Musach J, Pujana MA, Bibikova M, et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics. 2011;6(6):692–702.

    Article  CAS  Google Scholar 

  22. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30(10):1363–9.

    Article  CAS  Google Scholar 

  23. Kolde R, Märtens K, Lokk K, Laur S, Vilo J. seqlm: an MDL based method for identifying differentially methylated regions in high density methylation array data. Bioinformatics. 2016;32(17):2604–10.

    Article  CAS  Google Scholar 

  24. Wickham H. ggplot2. Wiley Interdisciplinary Reviews: Computational Statistics. 2011;3(2):180–5.

  25. Edgar R, Tan PPC, Portales-Casamar E, Pavlidis P. Meta-analysis of human methylomes reveals stably methylated sequences surrounding CpG islands associated with high gene expression. Epigenetics Chromatin. 2014;7(1):28.

    Article  Google Scholar 

  26. Tamaresis JS, Irwin JC, Goldfien GA, Rabban JT, Burney RO, Nezhat C, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155(12):4986–99.

    Article  Google Scholar 

  27. Lokk K, Modhukur V, Rajashekar B, Märtens K, Mägi R, Kolde R, et al. DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns. Genome Biol. 2014;15(4):3248.

    Article  Google Scholar 

  28. Rahmioglu N, Drong AW, Lockstone H, Tapmeier T, Hellner K, Saare M, et al. Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues. Epigenetics. 2017; (just-accepted).

  29. Grandi G, Mueller MD, Papadia A, Kocbek V, Bersinger NA, Petraglia F, et al. Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol. 2016;117:30–8.

    Article  CAS  Google Scholar 

  30. Barbosa CP, De Souza AB, Bianco B, Christofolini D. The effect of hormones on endometriosis development. Minerva Ginecol. 2011;63(4):375–86.

    Google Scholar 

  31. Samadieh Y, Favaedi R, Ramezanali F, Afsharian P, Aflatoonian R, Shahhoseini M. Epigenetic dynamics of HOXA10 gene in infertile women with endometriosis. Reprod Sci. 2018;1933719118766255.

  32. Dyson MT, Roqueiro D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet. 2014;10(3):e1004158.

    Article  Google Scholar 

  33. Saare M, Modhukur V, Suhorutshenko M, Rajashekar B, Rekker K, Sõritsa D, et al. The influence of menstrual cycle and endometriosis on endometrial methylome. Clin Epigenetics. 2016;8(1):2.

    Article  Google Scholar 

  34. Osaki M, Ma O, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9(6):667–76.

    Article  CAS  Google Scholar 

  35. Slomovitz BM, Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. 2012;18(21):5856–64.

    Article  CAS  Google Scholar 

  36. Fresno JV, Casado E, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.

    Article  Google Scholar 

  37. Hers I, Vincent EE, Tavaré JM. Akt signalling in health and disease. Cell Signal. 2011;23(10):1515–27.

    Article  CAS  Google Scholar 

  38. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003;2(4):336–42.

    Article  Google Scholar 

  39. IJBeBA-GS B. Pathways of O-glycan biosynthesis in cancer cells. 1999;1473(1):67–95.

  40. MJBeBA-GS F. Roles of mucin-type O-glycans in cell adhesion. Biochim Biophys Acta. 2002;1573(3):394–405.

    Article  Google Scholar 

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Acknowledgments

The authors have great appreciations for the kind support of Professor Saadi Khochbin in the generation of the methylome data. We also thank the gynecologist Dr. Fariba Ramazanali for preparing samples.

Funding

This project was partially supported by the Royan Institute (Grant No. 96000045).

Author information

Authors and Affiliations

  1. Laboratory of Bioinformatics and Systems Biology, Department of Bioinformatics, University of Tehran, Kish International Campus, Kish, Iran

    Nadia Barjaste & Ali Masoudi-Nejad

  2. Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Nadia Barjaste & Ali Masoudi-Nejad

  3. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Maryam Shahhoseini & Parvaneh Afsharian

  4. Department of Computer Engineering, Sharif University of Technology, Tehran, Iran

    Ali Sharifi-Zarchi

Authors
  1. Nadia Barjaste
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  2. Maryam Shahhoseini
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  4. Ali Sharifi-Zarchi
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  5. Ali Masoudi-Nejad
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Correspondence to Ali Masoudi-Nejad.

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The authors declare that they have no conflicts of interest in the research.

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Maryam Shahhoseini is a co-corresponding author.

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Barjaste, N., Shahhoseini, M., Afsharian, P. et al. Genome-wide DNA methylation profiling in ectopic and eutopic of endometrial tissues. J Assist Reprod Genet 36, 1743–1752 (2019). https://doi.org/10.1007/s10815-019-01508-8

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  • DOI: https://doi.org/10.1007/s10815-019-01508-8

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