Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis

English version

Autoři: Sahar Houshdaran ^aff001; Ashwini B. Oke ^aff001; Jennifer C. Fung ^aff001; Kim Chi Vo ^aff001; Camran Nezhat ^aff002; Linda C. Giudice ^aff001
Působiště autorů: University of California San Francisco, Dept. of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California, United States of America ^aff001; Camran Nezhat Institute, Palo Alto, California, United States of America ^aff002
Vyšlo v časopise: Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008601
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008601

Souhrn

Programmed cellular responses to cycling ovarian-derived steroid hormones are central to normal endometrial function. Abnormalities therein, as in the estrogen-dependent, progesterone-“resistant” disorder, endometriosis, predispose to infertility and poor pregnancy outcomes. The endometrial stromal fibroblast (eSF) is a master regulator of pregnancy success. However, the complex hormone-epigenome-transcriptome interplay in eSF by each individual steroid hormone, estradiol (E₂) and/or progesterone (P₄), under physiologic and pathophysiologic conditions, is poorly understood and was investigated herein. Genome-wide analysis in normal, early and late stage eutopic eSF revealed: i) In contrast to P₄, E₂ extensively affected the eSF DNA methylome and transcriptome. Importantly, E₂ resulted in a more open versus closed chromatin, confirmed by histone modification analysis. Combined E₂ with P₄ affected a totally different landscape than E₂ or P₄ alone. ii) P₄ responses were aberrant in early and late stage endometriosis, and mapping differentially methylated CpG sites with progesterone receptor targets from the literature revealed different but not decreased P₄-targets, leading to question the P₄-“resistant” phenotype in endometriosis. Interestingly, an aberrant E₂-response was noted in eSF from endometriosis women; iii) Steroid hormones affected specific genomic contexts and locations, significantly enriching enhancers and intergenic regions and minimally involving proximal promoters and CpG islands, regardless of hormone type and eSF disease state. iv) In eSF from women with endometriosis, aberrant hormone-induced methylation signatures were mainly due to existing DNA methylation marks prior to hormone treatments and involved known endometriosis genes and pathways. v) Distinct DNA methylation and transcriptomic signatures revealed early and late stage endometriosis comprise unique disease subtypes. Taken together, the data herein, for the first time, provide significant insight into the hormone-epigenome-transcriptome interplay of each steroid hormone in normal eSF, and aberrant E₂ response, distinct disease subtypes, and pre-existing epigenetic aberrancies in the setting of endometriosis, provide mechanistic insights into how endometriosis affects endometrial function/dysfunction.

Klíčová slova:

DNA methylation – endometrium – Gene expression – Gene regulation – Genetic loci – Chromatin – Methylation – Steroid hormones

Zdroje

1. Gargett CE, Chan RWS, Schwab KE. Endometrial stem cells. Curr Opin Obstet Gynecol. 2007;19: 377–83. doi: 10.1097/GCO.0b013e328235a5c6 17625422

2. Macklon NS, Brosens JJ. The Human Endometrium as a Sensor of Embryo Quality1. Biol Reprod. 2014;91. doi: 10.1095/biolreprod.114.122846 25187529

3. Vicent GP, Nacht AS, Font-mateu J, Castellano G, Gaveglia L, Beato M. Four enzymes cooperate to displace histone H1 during the first minute of hormonal gene activation. 2011; 845–862. doi: 10.1101/gad.621811 21447625

4. Heldring N, Isaacs GD, Diehl AG, Sun M, Cheung E, Ranish JA, et al. Multiple Sequence-Specific DNA-Binding Proteins Mediate Estrogen Receptor Signaling through a Tethering Pathway. Mol Endocrinol. 2011;25: 564–574. doi: 10.1210/me.2010-0425 21330404

5. Kittler R, Zhou J, Hua S, Ma L, Liu Y, Pendleton E, et al. A Comprehensive Nuclear Receptor Network for Breast Cancer Cells. Cell Rep. 2013;3: 538–551. doi: 10.1016/j.celrep.2013.01.004 23375374

6. Al-Sabbagh M, Lam EW-F, Brosens JJ. Mechanisms of endometrial progesterone resistance. Mol Cell Endocrinol. 2012;358: 208–215. doi: 10.1016/j.mce.2011.10.035 22085558

7. Piestrzeniewicz-Ulanska D, Brys M, Semczuk A, Jakowicki JA, Krajewska WM. Expression of TGF-beta type I and II receptors in normal and cancerous human endometrium. Cancer Lett. 2002;186: 231–9. Available: http://www.ncbi.nlm.nih.gov/pubmed/12213293 doi: 10.1016/s0304-3835(02)00351-8 12213293

8. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, et al. Gene Expression Analysis of Endometrium Reveals Progesterone Resistance and Candidate Susceptibility Genes in Women with Endometriosis. Endocrinology. 2007;148: 3814–3826. doi: 10.1210/en.2006-1692 17510236

9. Tamura I, Ohkawa Y, Sato T, Suyama M, Jozaki K, Okada M, et al. Genome-wide analysis of histone modifications in human endometrial stromal cells. Mol Endocrinol. 2014;28: 1656–1669. doi: 10.1210/me.2014-1117 25073104

10. Mazur EC, Vasquez YM, Li X, Kommagani R, Jiang L, Chen R, et al. Progesterone Receptor Transcriptome and Cistrome in Decidualized Human Endometrial Stromal Cells. Endocrinology. 2015;156: 2239–2253. doi: 10.1210/en.2014-1566 25781565

11. Vrljicak P, Lucas ES, Lansdowne L, Lucciola R, Muter J, Dyer NP, et al. Analysis of chromatin accessibility in decidualizing human endometrial stromal cells. FASEB J. 2018;32: 2467–2477. doi: 10.1096/fj.201701098R 29259032

12. Giudice LC. Endometriosis. N Engl J Med. 2010;362: 2389–2398. doi: 10.1056/NEJMcp1000274 20573927

13. Bulun SE, Cheng Y-H, Pavone ME, Xue Q, Attar E, Trukhacheva E, et al. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28: 36–43. doi: 10.1055/s-0029-1242991 20104427

14. Houshdaran S, Nezhat CR, Vo KC, Zelenko Z, Irwin JC, Giudice LC. Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis. Biol Reprod. 2016;95: 93–93. doi: 10.1095/biolreprod.116.140434 27535958

15. Houshdaran S, Zelenko Z, Irwin JC, Giudice LC. Human endometrial DNA methylome is cycle- dependent and is associated with gene expression regulation. Mol Endocrinol. 2014;28. doi: 10.1210/me.2013-1340 24877562

16. 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: 2. doi: 10.1186/s13148-015-0168-z 26759613

17. Vannuccini S, Clifton VL, Fraser IS, Taylor HS, Critchley H, Giudice LC, et al. Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome. Hum Reprod Update. 2016;22: 104–115. doi: 10.1093/humupd/dmv044 26395640

18. Aghajanova L, Horcajadas JA, Weeks JL, Esteban FJ, Nezhat CN, Conti M, et al. The Protein Kinase A Pathway-Regulated Transcriptome of Endometrial Stromal Fibroblasts Reveals Compromised Differentiation and Persistent Proliferative Potential in Endometriosis. Endocrinology. 2010;151: 1341–1355. doi: 10.1210/en.2009-0923 20068008

19. Aghajanova L, Tatsumi K, Horcajadas JA, Zamah AM, Esteban FJ, Herndon CN, et al. Unique Transcriptome, Pathways, and Networks in the Human Endometrial Fibroblast Response to Progesterone in Endometriosis. Biol Reprod. 2011;84: 801–815. doi: 10.1095/biolreprod.110.086181 20864642

20. Barragan F, Irwin JC, Balayan S, Erikson DW, Chen JC, Houshdaran S, et al. Human Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis. Biol Reprod. 2016;94. doi: 10.1095/biolreprod.115.136010 27075616

21. Bulun SE. Endometriosis. N Engl J Med. 2009;360: 268–279. doi: 10.1056/NEJMra0804690 19144942

22. Welboren W-J, van Driel MA, Janssen-Megens EM, van Heeringen SJ, Sweep FC, Span PN, et al. ChIP-Seq of ERα and RNA polymerase II defines genes differentially responding to ligands. EMBO J. 2009;28: 1418–1428. doi: 10.1038/emboj.2009.88 19339991

23. Hah N, Kraus WL. Hormone-regulated transcriptomes: Lessons learned from estrogen signaling pathways in breast cancer cells. Mol Cell Endocrinol. 2014;382: 652–664. doi: 10.1016/j.mce.2013.06.021 23810978

24. Kim JJ, Kurita T, Bulun SE. Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer. Endocr Rev. 2013;34: 130–162. doi: 10.1210/er.2012-1043 23303565

25. Aghajanova L, Giudice LC. Molecular evidence for differences in endometrium in severe versus mild endometriosis. Reprod Sci. 2011;18: 229–251. doi: 10.1177/1933719110386241 21063030

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: 4986–99. doi: 10.1210/en.2014-1490 25243856

27. Vasquez YM, Mazur EC, Li X, Kommagani R, Jiang L, Chen R, et al. FOXO1 is Required for Binding of PR on IRF4, Novel Transcriptional Regulator of Endometrial Stromal Decidualization. Mol Endocrinol. 2015;29: 421–433. doi: 10.1210/me.2014-1292 25584414

28. Jadhav RR, Ye Z, Huang R-L, Liu J, Hsu P-Y, Huang Y-W, et al. Genome-wide DNA methylation analysis reveals estrogen-mediated epigenetic repression of metallothionein-1 gene cluster in breast cancer. Clin Epigenetics. 2015;7: 13. doi: 10.1186/s13148-015-0045-9 25763113

29. Liu MH, Cheung E. Estrogen receptor-mediated long-range chromatin interactions and transcription in breast cancer. Mol Cell Endocrinol. 2014;382: 624–632. doi: 10.1016/j.mce.2013.09.019 24071518

30. Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, et al. Genome-wide analysis of estrogen receptor binding sites. Nat Genet. 2006;38: 1289–1297. doi: 10.1038/ng1901 17013392

31. Creighton CJ, Kent Osborne C, van de Vijver MJ, Foekens JA, Klijn JG, Horlings HM, et al. Molecular profiles of progesterone receptor loss in human breast tumors. Breast Cancer Res Treat. 2009;114: 287–299. doi: 10.1007/s10549-008-0017-2 18425577

32. Li L, Lee K-M, Han W, Choi J-Y, Lee J-Y, Kang GH, et al. Estrogen and progesterone receptor status affect genome-wide DNA methylation profile in breast cancer. Hum Mol Genet. 2010;19: 4273–4277. doi: 10.1093/hmg/ddq351 20724461

33. Widschwendter M, Siegmund KD, Müller HM, Fiegl H, Marth C, Müller-Holzner E, et al. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res. 2004;64: 3807–13. doi: 10.1158/0008-5472.CAN-03-3852 15172987

34. Lessey BA, Kim JJ. Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why. Fertil Steril. 2017;108: 19–27. doi: 10.1016/j.fertnstert.2017.05.031 28602477

35. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al. Expression Profiling of Endometrium from Women with Endometriosis Reveals Candidate Genes for Disease-Based Implantation Failure and Infertility. Endocrinology. 2003;144: 2870–2881. doi: 10.1210/en.2003-0043 12810542

36. Fazleabas A. Progesterone Resistance in a Baboon Model of Endometriosis. Semin Reprod Med. 2010;28: 075–080. doi: 10.1055/s-0029-1242997 20104431

37. Lessey BA, Palomino WA, Apparao K, Young SL, Lininger RA. Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women. Reprod Biol Endocrinol. 2006;4: S9. doi: 10.1186/1477-7827-4-S1-S9 17118173

38. Hamdan M, Dunselman G, Li TC, Cheong Y. The impact of endometrioma on IVF/ICSI outcomes: A systematic review and meta-analysis. Hum Reprod Update. 2015;21: 809–825. doi: 10.1093/humupd/dmv035 26168799

39. Singh N, Lata K, Naha M, Malhotra N, Tiwari A, Vanamail P. Effect of endometriosis on implantation rates when compared to tubal factor in fresh non donor in vitro fertilization cycles. J Hum Reprod Sci. 2014;7: 143–147. doi: 10.4103/0974-1208.138874 25191029

40. Garcia-Velasco JA, Fassbender A, Ruiz-Alonso M, Blesa D, D’Hooghe T, Simon C. Is endometrial receptivity transcriptomics affected in women with endometriosis? A pilot study. Reprod Biomed Online. 2015;31: 647–654. doi: 10.1016/j.rbmo.2015.07.014 26385059

41. Nilufer Rahmioglu, Karina Banasik, Paraskevi Christofidou, Rebecca Danning, Genevieve Galarneau, Ayush Giri, Stuart MacGregor, Sally Mortlock, Yadav Sapkota, Schork J Andrew Sobalska-Kwapis Marta, Lilja Stefansdottir, Constance Turman, Outi Uimari, Adach ZTK. Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions. biRxiv. 2018.

42. Kuivasaari P, Hippeläinen M, Anttila M, Heinonen S. Effect of endometriosis on IVF/ICSI outcome: stage III/IV endometriosis worsens cumulative pregnancy and live-born rates. Hum Reprod. 2005;20: 3130–3135. doi: 10.1093/humrep/dei176 16006468

43. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77: 1148–55. Available: http://www.ncbi.nlm.nih.gov/pubmed/12057720 doi: 10.1016/s0015-0282(02)03112-6 12057720

44. 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. doi: 10.1371/journal.pgen.1004158 24603652

45. Maekawa R, Tamura I, Shinagawa M, Mihara Y, Sato S, Okada M, et al. Genome-wide DNA methylation analysis revealed stable DNA methylation status during decidualization in human endometrial stromal cells. BMC Genomics. 2019;20. doi: 10.1186/s12864-019-5695-0 31035926

46. Laird PW. Principles and challenges of genome-wide DNA methylation analysis. Nat Rev Genet. 2010;11: 191. Available: doi: 10.1038/nrg2732 20125086

47. Lessey BA, Young SL. Homeostasis imbalance in the endometrium of women with implantation defects: The role of estrogen and progesterone. Semin Reprod Med. 2014;32: 365–375. doi: 10.1055/s-0034-1376355 24959818

48. Palomino WA, Tayade C, Argandoña F, Devoto L, Young SL, Lessey BA. The endometria of women with endometriosis exhibit dysfunctional expression of complement regulatory proteins during the mid secretory phase. J Reprod Immunol. 2018;125: 1–7. doi: 10.1016/j.jri.2017.10.046 29153978

49. Yoo JY, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, et al. KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci Rep. 2017;7. doi: 10.1038/s41598-017-04577-w 28754906

50. Stocks MM, Crispens MA, Ding T, Mokshagundam S, Bruner-Tran KL, Osteen KG. Therapeutically Targeting the Inflammasome Product in a Chimeric Model of Endometriosis-Related Surgical Adhesions. Reprod Sci. 2017;24: 1121–1128. doi: 10.1177/1933719117698584 28322132

51. Klemmt PAB, Carver JG, Kennedy SH, Koninckx PR, Mardon HJ. Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity. Fertil Steril. 2006;85: 564–572. doi: 10.1016/j.fertnstert.2005.08.046 16500320

52. Osteen KG, Bruner-Tran KL, Eisenberg E. Reduced progesterone action during endometrial maturation: A potential risk factor for the development of endometriosis. Fertil Steril. 2005;83: 529–537. doi: 10.1016/j.fertnstert.2004.11.026 15749474

53. Bruner-Tran KL, Eisenberg E, Yeaman GR, Anderson TA, McBean J, Osteen KG. Steroid and Cytokine Regulation of Matrix Metalloproteinase Expression in Endometriosis and the Establishment of Experimental Endometriosis in Nude Mice. J Clin Endocrinol Metab. 2002;87: 4782–4791. doi: 10.1210/jc.2002-020418 12364474

54. McKinnon B, Mueller M, Montgomery G. Progesterone Resistance in Endometriosis: an Acquired Property? Trends Endocrinol Metab. 2018;29: 535–548. doi: 10.1016/j.tem.2018.05.006 29934050

55. Garrido-Gomez T, Dominguez F, Quiñonero A, Diaz-Gimeno P, Kapidzic M, Gormley M, et al. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc Natl Acad Sci. 2017;114: E8468–E8477. doi: 10.1073/pnas.1706546114 28923940

56. Yang S, Fang Z, Suzuki T, Sasano H, Zhou J, Gurates B, et al. Regulation of Aromatase P450 Expression in Endometriotic and Endometrial Stromal Cells by CCAAT/Enhancer Binding Proteins (C/EBPs): Decreased C/EBPβ in Endometriosis Is Associated with Overexpression of Aromatase. J Clin Endocrinol Metab. 2002;87: 2336–2345. doi: 10.1210/jcem.87.5.8486 11994385

57. Attar E, Bulun SE. Aromatase and other steroidogenic genes in endometriosis: translational aspects. Hum Reprod Update. 2006;12: 49–56. doi: 10.1093/humupd/dmi034 16123052

58. Kitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Yamamoto T, et al. Expression of Aromatase Cytochrome P450 Protein and Messenger Ribonucleic Acid in Human Endometriotic and Adenomyotic Tissues but not in Normal Endometrium1. Biol Reprod. 1997;57: 514–519. doi: 10.1095/biolreprod57.3.514 9282984

59. Zeitoun K, Takayama K, Michael MD, Bulun SE. Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element. Mol Endocrinol. 1999;13: 239–253. doi: 10.1210/mend.13.2.0229 9973254

60. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489: 75–82. doi: 10.1038/nature11232 22955617

61. Andreu-Vieyra C, Lai J, Berman BP, Frenkel B, Jia L, Jones PA, et al. Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells. Mol Cell Biol. 2011;31: 4648–62. doi: 10.1128/MCB.05934-11 21969603

62. Green S, Walter P, Kumar V, Krust A, Bornert J-M, Argos P, et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986;320: 134–139. doi: 10.1038/320134a0 3754034

63. Curtis Hewitt S, Collins J, Grissom S, Deroo B, Korach KS. Global Uterine Genomics in Vivo: Microarray Evaluation of the Estrogen Receptor α-Growth Factor Cross-Talk Mechanism. Mol Endocrinol. 2005;19: 657–668. doi: 10.1210/me.2004-0142 15528273

64. Tanos T, Rojo LJ, Echeverria P, Brisken C. ER and PR signaling nodes during mammary gland development. Breast Cancer Res. 2012;14: 210. doi: 10.1186/bcr3166 22809143

65. Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Publ Gr. 2010;43. doi: 10.1038/ng.730 21151129

66. He HH, Meyer CA, Chen MW, Jordan VC, Brown M, Liu XS. Differential DNase I hypersensitivity reveals factor-dependent chromatin dynamics. Genome Res. 2012;22: 1015–25. doi: 10.1101/gr.133280.111 22508765

67. He HH, Meyer CA, Shin H, Bailey ST, Wei G, Wang Q, et al. Nucleosome dynamics define transcriptional enhancers. Nat Genet. 2010;42. doi: 10.1038/ng.545 20208536

68. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science (80-). 1995;270: 1491–1494. doi: 10.1126/science.270.5241.1491 7491495

69. Lupien M, Meyer CA, Bailey ST, Eeckhoute J, Cook J, Westerling T, et al. Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance. Genes Dev. 2010;24: 2219–27. doi: 10.1101/gad.1944810 20889718

70. Large MJ, Wetendorf M, Lanz RB, Hartig SM, Creighton CJ, Mancini MA, et al. The Epidermal Growth Factor Receptor Critically Regulates Endometrial Function during Early Pregnancy. Stewart C, editor. PLoS Genet. 2014;10: e1004451. doi: 10.1371/journal.pgen.1004451 24945252

71. Erikson DW, Chen JC, Piltonen TT, Conti M, Irwin JC, Giudice LC, et al. Inhibition of epidermal growth factor receptor restores decidualization markers in stromal fibroblasts from women with endometriosis. J Endometr. 2014;6: 196–211. doi: 10.5301/je.5000198

72. Berno V, Amazit L, Hinojos C, Zhong J, Mancini MG, Sharp ZD, et al. Activation of estrogen receptor-alpha by E2 or EGF induces temporally distinct patterns of large-scale chromatin modification and mRNA transcription. PLoS One. 2008;3: e2286. doi: 10.1371/journal.pone.0002286 18509470

73. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122: 262–263. doi: 10.1016/s0002-9378(16)33500-1 1155504

74. American Society for Reproductive AS for R. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67: 817–821. doi: 10.1016/s0015-0282(97)81391-x 9130884

75. Sheldon E, Vo KC, McIntire RA, Aghajanova L, Zelenko Z, Irwin JC, et al. Biobanking human endometrial tissue and blood specimens: standard operating procedure and importance to reproductive biology research and diagnostic development. Fertil Steril. 2011;95: 2120–2122.e12. doi: 10.1016/j.fertnstert.2011.01.164 21371706

76. Irwin JC, Kirk D, King RJB, Quigley MM, Gwatkin RBL. Hormonal regulation of human endometrial stromal cells in culture: an in vitro model for decidualization. Fertil Steril. 1989;52: 761–768. doi: 10.1016/s0015-0282(16)61028-2 2806617

77. Bell SC, Jackson JA, Ashmore J, Zhu HH, Tseng L. Regulation of Insulin-Like Growth Factor-Binding Protein-1 Synthesis and Secretion by Progestin and Relaxin in Long Term Cultures of Human Endometrial Stromal Cells*. J Clin Endocrinol Metab. 1991;72: 1014–1024. doi: 10.1210/jcem-72-5-1014 1708779

78. Campan M, Weisenberger DJ, Trinh B, Laird PW. MethyLight. Methods in molecular biology (Clifton, NJ). 2009. pp. 325–337. doi: 10.1007/978-1-59745-522-0_23 18987824

79. Triche TJ, Weisenberger DJ, Van Den Berg D, Laird PW, Siegmund KD. Low-level processing of Illumina Infinium DNA Methylation BeadArrays. Nucleic Acids Res. 2013;41: e90–e90. doi: 10.1093/nar/gkt090 23476028

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