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Cited by 82Endometriosis Research and TreatmentEpigenetics and DNA MethylationGynecological conditions and treatments

Altered genome-wide methylation in endometriosis

Open access
Naqvi, Hanyia, Ilagan, Ysabel, Krikun, Graciela, Taylor, Hugh S.·2014·Reproductive Sciences
DOI 10.1177/1933719114532841PMC PMC5933183
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Abstract

Endometriosis has been associated with aberrant methylation in the eutopic endometrium. Using a genome-wide methylation array, we identified differentially methylated genes in the endometrium from women with or without endometriosis. One hundred and twenty genes were significantly altered by >1.5-fold. In all, 59 genes were significantly hypermethylated and 61 genes were significantly hypomethylated. Changes in gene expression associated with the altered methylation status were validated using quantitative real-time polymerase chain reaction. A limited number of candidate genes are selectively methylated in the endometrium of women with endometriosis. Several genes not previously associated with endometriosis are aberrantly methylated and expressed. These include O-6-methylguanine-DNA methyltransferase, dual specificity phosphatase 22, cell division cycle associated 2, inhibitor of DNA binding 2, retinoblastoma binding protein 7, bone morphogenetic protein receptor, type 1B, tumor necrosis factor receptor 1B, zinc finger protein receptor 681, immunoglobulin superfamily, member 21, and tumor protein 73. Aberrant DNA methylation and gene expression of these genes may contribute to abnormal regulation of endometrial cell proliferation and function in women.

AI snapshot

Written from the paper’s full text.

TL;DR

Genome-wide methylation profiling of eutopic endometrium found 120 genes altered by >1.5-fold in women with endometriosis versus controls, including 59 hypermethylated and 61 hypomethylated genes. Ten novel candidate genes were validated by qRT-PCR, with mostly concordant but sometimes non-significant expression changes.

Key findings

  • Of 27,578 genes on the methylation array, 120 genes were significantly altered by ≥1.5-fold; 59 were significantly hypermethylated and 61 significantly hypomethylated.
  • Selected hypermethylated genes included MGMT, DUSP22, CDCA2, ID2, and RBBP7. qRT-PCR showed decreased expression for MGMT (0.3-fold, P = .015), DUSP22 (0.3-fold, P = .039), CDCA2 (0.06-fold, P = .03), and ID2 (0.4-fold, P = .004); RBBP7 was decreased 0.3-fold but did not reach significance (P = .069).
  • Selected hypomethylated genes included BMPR1B, TNFRSF1B, ZNF681, IGSF21, and TP73. Expression was generally increased but not consistently significant: ZNF681 increased 4.8-fold (P = .003), BMPR1B increased 2.49-fold (P > .05), TNFRS1B increased 1.3-fold (P > .05), IGSF21 decreased 0.002-fold (P = .03), and TP73 changed 0.346-fold (P > .05).
  • DNMT1 expression was increased and its methylation altered by 1.13-fold; DNMT3a and DNMT3b expression was repressed and methylation altered by 1.04-fold and 1.01-fold, respectively, with none meeting threshold or significance. HOXA10 expression was repressed and methylation altered by 1.3-fold (P = .008), below the study threshold. No significant methylation changes were found for PR-B, CYP19A1, SF1, COX2, or ER-b.

Methods

  • Endometrial biopsies were obtained from 13 reproductive-age patients undergoing surgical treatment: 7 with endometriosis and 6 endometriosis-free controls. Patients had not used hormone-based therapies for at least 3 months before collection; diagnosis was histologically confirmed.
  • Genome-wide methylation was assessed using the Illumina Infinium HumanMethylation27 RevB Beadchip after bisulfite conversion, with GenomeStudio used for bioinformatics and statistical analysis.
  • Methylation results were validated by quantitative real-time PCR for 10 selected genes, standardized to β-actin, with relative expression calculated by 2^−ΔΔCT and P ≤ .05 considered significant.

Limitations

  • The paper states that the arbitrary 1.5-fold threshold is likely too restrictive to identify all epigenetically altered genes with a possible role in endometriosis, noting HOXA10 at 1.3-fold (P = .008) fell below this cutoff.
  • The paper states it did not find significant methylation changes in several genes previously reported in endometriosis (PR-B, CYP19A1, SF1, COX2, ER-b), and suggests differences may be due to sampling eutopic versus ectopic endometrium, patient/disease characteristics, arbitrary cutoff thresholds, or targeted loci.
  • Evident from the text: the sample is small (n = 13; 7 cases, 6 controls), and only 10 selected genes were validated by qRT-PCR, with several expression changes not statistically significant.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1177/1933719114532841

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 43 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    61 genes were significantly hypomethylated in endometriosis.

    “In all, 59 genes were significantly hypermethylated and 61 genes were significantly hypomethylated.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.
  • Findingown data

    TNFRSF1B was hypomethylated in endometriosis.

    “Genes with decreased methylation include BMPR1B, TNFRSF1B, ZNF681, IGSF21, and TP73.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.
  • Findingown data

    CDCA2 was hypermethylated in endometriosis.

    “Examples of hypermethylated genes include MGMT, DUSP22, CDCA2, ID2, and RBBP7.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.
  • Findingown data

    Expression of DUSP22 was decreased by 0.3-fold (P=.039) in endometriosis compared to controls.

    “Expression of DUSP22 was decreased by 0.3-fold (P ¼ .039),”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.
  • Findingown data

    BMPR1B was highly expressed in the endometrium of females with endometriosis (2.49-fold, P > .05).

    “BMPR1B was highly expressed in the endometrium of females with endometriosis (2.49-fold, P > .05).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.
  • May combine two claims. 28
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    RBBP7 expression was decreased by 0.3-fold but did not reach significance (P=.069).

    “however, RBBP7 while decreased by 0.3-fold did not reach significance (P ¼ .069).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • The quote only partly states this claim.

    Findingown data

    Genome-wide methylation array identified differentially methylated genes in the eutopic endometrium from women with or without endometriosis.

    “Using a genome-wide methylation array, we identified differentially methylated genes in the endometrium from women with or without endometriosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    Expression was generally increased in genes noted to be hypomethylated, but this trend was not consistently significant.

    “Expression was generally increased in genes noted to be hypomethylated; however, this trend was not consistently significant (Figure 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    Expression of DNMT3a and DNMT3b was repressed and methylation altered by 1.04-fold and 1.01-fold, respectively.

    “Expression of DNMT3a and DNMT3b was repressed and methylation altered by 1.04-fold and 1.01-fold, respectively.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    DNMT1 expression was increased and its methylation was altered by 1.13-fold in this study.

    “Here, DNMT1 expression was increased and its methylation was altered by 1.13-fold.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    None of the changes in DNMT methylation met the predetermined threshold or reached statistical significance.

    “None of the changes in DNMT methylation met our predetermined threshold or reached statistical significance.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    Numerous genes where altered methylation in endometriosis has been previously established were also identified in this array, although some were below the selected threshold.

    “Numerous genes, where altered methylation in endometriosis has been previously established, were also identified in this array, although some were below our selected threshold.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    Many of the genes identified by Borghese et al as having significantly altered methylation in endometriosis were also identified in our array; these include MAFB, HOXD10, and HOXD11.

    “Many of the genes identified by Borghese et al as having significantly altered methylation in endometriosis were also identified in our array; these include MAFB, HOXD10, and HOXD11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Borghese B, Barbaux S, Mondon F, et al. Research resource: genome-wide profiling of methylated promoters in endometriosis reveals a subtelomeric location of hypermethylation. Mol Endocrinol. 2010;24(9):1872–1885. source

      Not checked in the free run.

    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    Most of the methylated genes whose expression we examined were repressed; similarly, most of the genes with diminished methylation showed increased expression.

    “Indeed, most of the methylated genes whose expression we examined were repressed; similarly, most of the genes with diminished methylation showed increased expression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingown data

    In this study, HOXA10 expression was repressed and methylation was altered by 1.3-fold (P=.008).

    “Here, HOXA10 expression was repressed and methylation was altered by 1.3fold (P ¼ .008).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Findingreasoning

    Typically enhanced methylation was associated with decreased expression of a gene, although diminished methylation correlated with higher levels of gene expression.

    “Typically enhanced methylation was associated with decreased expression of a gene, although diminished methylation correlated with higher levels of gene expression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The endometriosis-free controls were truly free of endometriosis.

  • May combine two claims.

    Premisecitation

    Gene expression is commonly altered in endometriosis and in the eutopic endometrium of women with the disease.

    “It is clear that gene expression is commonly altered in endometriosis and in the eutopic endometrium of women with the disease.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Vigano P, Somigliana E, Vignali M, Busacca M, Blasio AM. Genetics of endometriosis: current status and prospects. Front Biosci. 2007;12:3247–3255. source

      Not checked in the free run.

    • cites [16] Bischoff F, Simpson JL. Genetics of endometriosis: heritability and candidate genes. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):219–232. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Methylation of CpG islands in a gene's promoter region may downregulate or transcriptionally silence that gene's expression.

    “If the CpG islands of the promoter region for a particular gene are methylated, the expression of that gene may be downregulated or transcriptionally silenced;”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Ng HH, Bird A. DNA methylation and chromatin modification. Curr Opin Genet Dev. 1999;(2):158–163. source

      Not checked in the free run.

    • cites [21] Robertson KD. DNA methylation and chromatin-unraveling the tangled web. Oncogene. 2002;21(35):5361–5379. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The specificity of the amplified transcript was confirmed by melting curve analysis.

    “The specificity of the amplified transcript was confirmed by a melting curve analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Methylated and nonmethylated DNA standards were used as positive and negative controls to determine the efficiency of bisulfite conversion.

    “Methylated and nonmethylated DNA standards were used as positive and negative controls to determine the efficiency of conversion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Estrogen signaling is likely epigenetically amplified in endometriosis leading to increased proliferation and resistance to apoptosis.

    “Estrogen signaling is likely epigenetically amplified in endometriosis leading to increased proliferation and resistance to apoptosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Both Ki-67 and Bcl-2 expression have been closely linked to estrogen receptor level.

    “Both Ki-67 and Bcl-2 expression have been closely linked to estrogen receptor level.29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Risberg B, Karlsson K, Abeler V, Lagrelius A, Davidson B, Karlsson MG. Dissociated expression of Bcl-2 and Ki-67 in endometrial lesions: diagnostic and histogenetic implications. Int J Gynecol Pathol. 2002;21(2):155–160. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) are highly expressed in endometrial lesions.

    “DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) are highly expressed in endometrial lesions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Wu Y, Strawn E, Basir Z, Halverson G, Guo SW. Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis. Fertil Steril. 2007;87(1):24–32. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Activation and/or aberrant expression of a gene can contribute to the development of endometriosis, cancers, or other abnormalities.

    “Activation and/or aberrant expression of a gene can contribute to the development of endometriosis, cancers, or other abnormalities.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–463. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Increased proliferation, invasion, and resistance to apoptosis may potentially explain the pathogenesis of endometriosis; several of these characteristic behaviors have been previously linked to epigenetic alterations.

    “Increased proliferation, invasion, and resistance to apoptosis may potentially explain the pathogenesis of endometriosis; several of these characteristic behaviors of endometriosis have been previously linked to epigenetic alterations.23,24”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Izawa M, Taniguchi F, Terakawa N, Harada T. Epigenetic aberration of gene expression in endometriosis. Front Biosci (Elite Ed). 2013;5:900–10. source

      Not checked in the free run.

    • cites [24] Park JS, Lee JH, Kim M, Chang HJ, Hwang KJ, Chang KH. Endometrium from women with endometriosis shows increased proliferation activity. Fertil Steril. 2009;92(4):1246–1249. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    qRT-PCR reactions for each gene were performed in duplicate and repeated 3 times.

    “The reactions for each gene were performed in duplicate and repeated 3 times.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    The study provides a comprehensive survey of DNA methylation in the endometrium of women with endometriosis.

    “In this study, we provide a comprehensive survey on the extent of DNA methylation in the endometrium of women with endometriosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The eutopic endometrium samples from the women with endometriosis in this study are representative of women with endometriosis generally.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ZNF681 contains a classical C2H2 (Kruppel) zinc finger motif and functions as an activator and repressor of transcription, regulating proliferation, differentiation, and development.

    “Zinc finger protein 681 contains a classical C 2 H 2 (Kruppel) zinc finger motif and functions as an activator and repressor of transcription, regulating proliferation, differentiation, and development.38,49”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Dang DT, Pevsner J, Yang VW. The biology of the mammalian Krüppel-like family of transcription factors. Int J Biochem Cell Biol. 2000;32(11–12): 1103–1121. source

      Not checked in the free run.

    • cites [49] Buck-Koehntop BA, Stanfield RL, Ekiert DC, et al. Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso. Proc Natl Acad Sci USA. 2012;109(38):15229–15234. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bcl-2 inhibits apoptosis in the endometrium and endometrial lesions.

    “Bcl-2 is a regulator of the programmed cell death process and inhibits apoptosis in the endometrium and the endometrial lesions.28,29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Korsmeyer SJ. BCL-2 gene family and the regulation of programmed cell death. Cancer Res. 1999;59(7 suppl):1693s–1700s.

      Not checked in the free run.

    • cites [29] Risberg B, Karlsson K, Abeler V, Lagrelius A, Davidson B, Karlsson MG. Dissociated expression of Bcl-2 and Ki-67 in endometrial lesions: diagnostic and histogenetic implications. Int J Gynecol Pathol. 2002;21(2):155–160. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Unmethylated CpG islands in a gene's promoter region are typically associated with higher expression of that gene.

    “in contrast, if the CpG islands in the promoter region remain unmethylated, the gene is typically more highly expressed.20,21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Ng HH, Bird A. DNA methylation and chromatin modification. Curr Opin Genet Dev. 1999;(2):158–163. source

      Not checked in the free run.

    • cites [21] Robertson KD. DNA methylation and chromatin-unraveling the tangled web. Oncogene. 2002;21(35):5361–5379. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher expression of estrogen receptor amplifies estrogenic effects and the proliferative capacity of endometrial cells.

    “Higher expression of estrogen receptor amplifies estrogenic effects and the proliferative capacity of endometrial cells.26,27”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Xue Q, Lin Z, Yin P, et al. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis. J Clin Endocrinol Metab. 2007;92(8):3261–3267. source

      Not checked in the free run.

    • cites [27] Xue Q, Lin Z, Cheng YH, et al. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod. 2007;77(4):681–687. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High levels of expression of DNMTs can lead to transcriptional activation or silencing of critical genes involved in regulating cell growth and apoptosis, thereby resulting in the survival of endometrial cells.

    “High levels of expression of DNMTs can lead to transcriptional activation or silencing of critical genes involved in regulating cell growth and apoptosis, respectively, thereby resulting in the survival of endometrial cells.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Wu Y, Strawn E, Basir Z, Halverson G, Guo SW. Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis. Fertil Steril. 2007;87(1):24–32. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    DNA methylation is a mechanism that likely leads to altered gene expression in endometriosis and appears to be selective, limited to a relatively small number of genes.

    “DNA methylation is a mechanism that likely leads to altered gene expression in endometriosis and appears to be selective, limited to a relatively small number of genes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The eutopic endometrium samples from the women with endometriosis in this study are representative of women with endometriosis generally.

  • May combine two claims.

    Premisecitation

    Hypermethylation of MGMT has been reported to decrease apoptotic responses to DNA damage by TP73 and cell proliferation regulation by RBBP7, which in combination with aberrant expression of HOXA10, increase susceptibility for endometriosis.

    “The hypermethylation of methyltransferase (MGMT) has been reported to decrease apoptotic responses to DNA damage by TP73 and cell proliferation regulation by RBBP7, which in combination with the aberrant expression of HOXA10, increase the susceptibility for endometriosis.12,[41][42][43][44][45][46][47][48]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo SW. 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):371–380. source

      Not checked in the free run.

    • cites [41] Wang Y, He X, Yu Q, Eng C. Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas. Hum Mol Genet. 2013;22(11):2263–2272. source

      Not checked in the free run.

    • cites [42] Jacobs DI, Hansen J, Fu A, et al. Methylation alterations at imprinted genes detected among long-term shiftworkers. Environ Mol Mutagen. 2013;54(2):141–146. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ki-67 is highly expressed in endometriosis.

    “Ki-67 is a nuclear protein involved in cellular proliferation and highly expressed in endometriosis.24”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Park JS, Lee JH, Kim M, Chang HJ, Hwang KJ, Chang KH. Endometrium from women with endometriosis shows increased proliferation activity. Fertil Steril. 2009;92(4):1246–1249. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The assembly of a functional transcription initiation complex may be prevented by altered methylation.

    “The assembly of a functional transcription initiation complex may be prevented by altered methylation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The level of HOXA10 epigenetic alteration was below the arbitrary threshold, suggesting that other genes may have alterations in methylation that regulate the development of this disease.

    “This level of epigenetic alteration was below our arbitrary threshold, suggesting that other genes may have alterations in methylation that regulate the development of this disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HOXA10 expression is lower in the endometrium of women with endometriosis and is abnormally methylated.

    “We have previously shown that HOXA10 expression is lower in the endometrium of women with endometriosis and is abnormally methylated.44,53,54”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [44] Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80(1):79–85. source

      Not checked in the free run.

    • cites [53] Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–2034. source

      Not checked in the free run.

    • cites [54] Kim JJ, Taylor HS, Lu Z, et al. Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 2007;13(5):323–332. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Altered methylation in either direction implies that the mechanisms responsible may be directed by multiple pathways and vary with the type and stage of disease.

    “Altered methylation in either direction implies that the mechanisms responsible may be directed by multiple pathways and vary with the type and stage of disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Changes in gene expression are context dependent and not simply the result of increased expression of a single methylating enzyme.

    “It is apparent that the changes in gene expression are context dependent and not simply the result of increased expression of a single methylating enzyme.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A precise understanding of epigenetics may provide a novel approach to the treatment of endometriosis.

    “A precise understanding of epigenetics may provide a novel approach to the treatment of endometriosis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The eutopic endometrium samples from the women with endometriosis in this study are representative of women with endometriosis generally.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Methylation that prevents the binding of a transcriptional repressor could have an opposite effect.

    “Alternatively, methylation that prevents the binding of a transcriptional repressor could have an opposite effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Methylation and demethylation are both common in endometriosis, making the broad use of agents that alter methylation in a single direction impractical.

    “Here, we identify epigenetic alterations in endometriosis; however, methylation and demethylation are both common, making the broad use of agents that alter methylation in a single direction impractical.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The eutopic endometrium samples from the women with endometriosis in this study are representative of women with endometriosis generally.

  • May combine two claims.

    Premisecitation

    Current treatments for endometriosis have limited long-term success and frequent side effects.

    “These treatments have limited long-term success with frequent side effects.[56][57][58][59]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal antiinflammatory drugs for pain in women with endometriosis. Cochrane Database Syst. 2009;(2):CD004753. source

      Not checked in the free run.

    • cites [57] Al Kadri H, Hassan S, Al-Fozan HM, Hajeer A. Hormone therapy for endometriosis and surgical menopause. Cochrane Database Syst. 2009;(1):CD005997. source

      Not checked in the free run.

    • cites [58] Nawathe A, Patwardhan S, Yates D, Harrison GR, Khan KS. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG. 2008;115(7):818–822. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Patient/disease characteristics, arbitrary cutoff thresholds, and location of targeted loci may have varied between studies.

    “Patient/disease characteristics, arbitrary cutoff thresholds, and location of targeted loci may have varied between studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Differences between our data and other published studies may be due to the ability of targeted assessment to identify small but meaningful areas of DNA methylation not identified in the array.

    “Differences between our data and other published studies may be due to the ability of targeted assessment to identify small but meaningful areas of DNA methylation not identified in the array.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    After careful characterization, the extent of epigenetic regulation may be a useful marker of disease as it is detectable in eutopic endometrium.

    “After careful characterization, the extent of epigenetic regulation may be a useful marker of disease as it is detectable in eutopic endometrium.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The eutopic endometrium samples from the women with endometriosis in this study are representative of women with endometriosis generally.
42 of 42

  • The paper relies on this without support.

    The eutopic endometrium samples from the women with endometriosis in this study are representative of women with endometriosis generally.

    “Endometrial biopsies were isolated from 13 reproductive-age patients undergoing surgical treatment of endometriosis (n ¼ 7) or endometriosis-free controls (n ¼ 6).”

  • The paper relies on this without support.

    The endometriosis-free controls were truly free of endometriosis.

    “Endometrial biopsies were isolated from 13 reproductive-age patients undergoing surgical treatment of endometriosis (n ¼ 7) or endometriosis-free controls (n ¼ 6).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Naqvi et al. observed five hypermethylated (MGMT, DUSP22, CDCA2, ID2, RBBP7) and five hypomethylated (TNFRSF1B, MBPR1B, ZNF681, IGSF21, TP73) genes in eutopic endometrium of endometriosis patients compared with endometriosis-free controls.

    “For example, Naqvi et al. (26) observed five hypermethylated (MGMT, DUSP22, CDCA2, ID2, and RBBP7) and five hypomethylated (TNFRSF1B, MBPR1B, ZNF681, IGSF21, and TP73) genes in eutopic endometrium of patients compared with endometriosis-free control subjects.”

    From Biomarkers in endometriosis: Challenges and opportunities (2017) · cites this paper as [26]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Table 2 is described as reporting expression changes, but reports methylation changes

    Minor

    The Results section says Table 2 lists fold-change ratios and statistical significance for gene expression. Table 2 instead labels those values as methylation status and methylation fold-change ratios; for example, its MGMT ratio is 2.220, whereas the reported expression change is 0.3-fold.

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Related

Authors
Naqvi, H., Ilagan, Y., Krikun, G., & Taylor, H. S.
Affiliations
Yale University (US)
Corresponding author
Taylor, Hugh S.
ORCID
Venue
Reproductive Sciences
Publisher
Springer Science and Business Media LLC
Published
2014-10
Volume
21
Issue
10
Pages
1237-1243
ISSN
  • 1933-7191 (ISSN-L)
  • 1933-7205
DOI
10.1177/1933719114532841
PMC
PMC5933183
OpenAlex
W2050152897
Semantic Scholar
18d7993d187927ed4de8674fa6f864bc8d26ab1a
Cited by
82
References
62
Citations by year
2026: 3 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 10 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 6 · 2015: 8 · 2014: 1
FWCI
8.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Reproductive Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NIH U54, HD052668, NIH U54 HD052668)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD052668)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gynecological conditions and treatments
Keywords
endometriosis, DNA methylation, differentially methylated genes, eutopic endometrium, hypermethylation, hypomethylation, gene expression, O6-methylguanine-DNA methyltransferase, endometrial proliferation
MeSH terms
Endometriosis, Female, Humans, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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