Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues

Rahmioğlu, Nilüfer; Lockstone, Helen; Tapmeier, Thomas T.; Hellner, Karin; Saare, Merli; Laisk-Podar, Triin; Dew, Christine; Tough, Emily; Nicholson, George; Peters, Maire; Morris, Andrew P.; Lindgren, Cecilia M.; Becker, Christian M.; Zondervan, Krina T.

doi:10.1080/15592294.2017.1367475

Cited by 34 publications

(45 citation statements)

References 67 publications

(57 reference statements)

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“…After a linear reduction of the variability for more than 30000 expressed genes, the control samples cluster together in a small group. The dispersion of the samples in the PCA analysis is lower compared to other tissue expression profiles using the same exploratory analysis [61]. In contrast, PTB chorioamniotic expression analysis revealed a more diverse group, further stressing the heterogeneity of this condition.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Pereyra

Bertoni

Sosa

et al. 2018

Preprint

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15 16 Short title: Transcriptomic analysis of severe preterm birth 17 Key words: RNA-seq, preterm birth, gestational age, biomarkers 18 2 19Abstract 20 Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results of 21 the interaction of both genetic and environmental components and constitutes a complex 22 multifactorial syndrome. Transcriptome analysis of PTB has proved challenging because of the 23 multiple causes of PTB and the numerous maternal and fetal gestational tissues that must interact 24 to facilitate parturition. A common pathway of labor and PTB may be the activation of fetal 25 membranes. In this work, chorioamnion membranes from severe preterm and term fetus were 26 analyzed using RNA sequencing. A total of 270 genes were differentially expressed (DE): 252 27 were up-regulated and 18 were down-regulated in the severe preterm compared to the term births. 28 We found great gene expression homogeneity in the control samples, and not in severe preterm 29 samples. In this work, we identified up-regulated pathways that were previously suggested as 30 leading to PTB like immunological and inflammatory paths. New pathways that were not 31 identified in preterm like the hemopoietic path appeared up-regulated in preterm membranes. A 32 group of 18 down-regulated genes discriminates between term and severe preterm cases. These 33 genes potentially characterize a severe preterm transcriptome pattern and therefore are candidate 34 genes for understanding the syndrome. Some of the down-regulated genes are involved in the 35 nervous system, morphogenesis (WNT-1, DLX5, PAPPA2) and ion channel complexes (KCNJ16, 36 KCNB1), making them good candidates as biomarkers of PTB.37 The identification of this DE gene pattern may help to develop a multi-gene disease classifier.38 These markers were generated in an admixtured South American population where PTB has a high 39 incidence. Since genetic background may impact differentially in different populations it is 40 mandatory to include populations like South American and African ones that are usually excluded 3 41 from high throughput approaches. These classifiers should be compared to those in other 42 populations to get a global landscape of PTB. 43 44 Introduction 45 Preterm birth (PTB), defined as the delivery of an infant before 37 weeks of completed gestation, 46 is a worldwide health problem and remains the leading cause of global perinatal morbidity and 47 mortality [1][2][3]. PTB is a complex, multifactorial syndrome comprised of multiple clinical 48 subtypes that can be defined as either 'spontaneous' or 'medically indicated' [4,5]. 70 % of PTB 49 cases are idiopathic; 5 % are due to the spontaneous onset of labor (sPTB) and the remaining 25 50 % are consequence of the preterm premature rupture of membranes (PPROM) [5,6]. PTB has also 51 been stratified according to gestational age (GA); neonates born between 24 and 33 weeks (severe 52 PTB) are at higher risk of death, and diseases later in life, than moderate PTB (GA betwee...

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Pereyra

Bertoni

Sosa

et al. 2018

Preprint

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“…Variability between lesions within person has been well-documented 16 and future research should investigate variability of DNAm age between lesions within an individual. While all of the lesions studied here were endometriomas, peritoneal disease presents with different colored lesions that are thought to represent a continuum from younger to older disease 25 , a hypothesis that could be explored using DNAm age.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study found a correlation of 0.8 between DNAm age and chronological age in uterine endometrium when all of the samples came from the same menstrual time point (LH+7, or 7 days after the surge in luteinizing hormone) 15 , but our correlation was unchanged if we stratified by menstrual phase (LH+8), or by endometriosis status. We next tested the effect of menstrual phase on DNAm age because menstrual phase is known to affect DNA methylation 16 . Each of the healthy controls donated two samples, one during the early secretory phase and the second during mid-secretory phase of the same menstrual period 17 .…”

Section: Endometriosis Does Not Affect Dna Methylation Age Of Eutopicmentioning

confidence: 99%

Epigenetic age provides insight into tissue origin in endometriosis

Leap¹,

Yotova

Horvath³

et al. 2019

Preprint

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Background: Endometriosis is a common reproductive disease with a heterogeneous presentation. Classification attempts have thus far not offered insight into its cause or its symptoms. Endometriosis may result from the migration of shed endometrium to the peritoneal cavity. However, there are cases reported in girls without uteruses and men. While a non-retrograde menstruation origin of ectopic tissue is certain in these cases, we propose using DNA methylation age (DNAm age) to distinguish between retrograde and non-retrograde etiologies.Methods: Using publicly available DNA methylation data and Horvath's pan-tissue epigenetic clock, we compared DNAm age and epigenetic age acceleration (EAA) of ectopic lesions to eutopic endometrium of diseased and control endometrium. We examined EAA in cancer metastasis and teratomas to control for migration and developmental origin.Results: Disease status does not change DNAm age of eutopic endometrium, but the effect of ectopic status was profound: -16.88 years (p = 4.82 x 10 -7 ). There were no differences between EAA of primary/metastatic tumor pairs, suggesting that the observed effect is not due to migration. Immature or mature teratoma compartments decreased DNAm age by 9.44 and 7.40 years respectively, suggesting that developmental state correlates with DNAm age. Conclusions:Ectopic endometriotic tissue exhibits decelerated DNAm age, similar to that observed in teratomas composed of multipotent tissue. The migration process does not change DNAm age and eutopic endometrium is concordant with chronological age regardless of disease status. We conclude that DNAm age of ectopic lesions can classify endometriosis into distinct subtypes that may be clinically relevant.

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“…FENOX was built on experience and feedback we received from patients and research nurses during a previous study (a study to identify possible biomarkers in women with Endometriosis at Oxford18). In addition, the research objectives were set in accordance with research priorities identified through the James Lind Alliance Priority Setting Partnership (PSP) for endometriosis, in which we participate 19.…”

Section: Methods and Analysismentioning

confidence: 99%

“…As this is a prospective sample and data collection study, there is no randomisation of patients as all women will undergo surgery as part of their routine clinical management. As previously,18 we will use SPSS, GraphPad Prism, STATA and R for analysis, and employ t-tests, analysis of variance (ANOVA), correlation coefficient analysis and similar methods. We plan to use multivariate logistic regression models in comparisons of endometriosis cases with controls, and fibroid cases with controls, adjusting for confounders relevant to the hypothesis being tested.…”

Section: Interventionsmentioning

confidence: 99%

Protocol for a longitudinal, prospective cohort study investigating the biology of uterine fibroids and endometriosis, and patients’ quality of life: the FENOX study

et al. 2020

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IntroductionMillions of women suffer from the consequences of endometriosis and uterine fibroids, with fibroids the cause for over 50% of hysterectomies in the USA, and direct costs for their treatment estimated at between US$4 and US$9 billion. Endometriosis commonly affects millions of women worldwide predominantly during reproductive age, with severe menstrual and non-menstrual pain and subfertility the main symptoms. Due to the ‘unhappy triad’ of endometriosis—lack of awareness, lack of clinically relevant biomarkers and the unspecific nature of symptoms—women wait on average for 8–12 years before the definitive endometriosis diagnosis is made. Treatment options for both conditions are not satisfactory at the moment, especially with a view to preserving fertility for the women and families affected. In the Fibroids and Endometriosis Oxford (FENOX) study, we combine the investigation of fibroids and endometriosis, and plan to collect high-quality tissue samples and medical data of participants over a time frame of 5 years after surgical intervention.Methods and analysisBiological samples such as blood, saliva, urine, fat, peritoneal fluid and—if found—endometrial tissue or fibroids as well as detailed clinical and intraoperative data will be collected from women undergoing surgery and participating in the study after informed consent. We plan to recruit up to 1200 participants per disease arm (ie, endometriosis and uterine fibroids) over 5 years. Participants will fill in detailed and validated questionnaires on their medical history and quality of life, with follow-ups for 5 years. Enrolment started on 2 April 2018, and FENOX will close on 31 March 2028. We will analyse the biological samples using state-of-the-art molecular biology methods and correlate the findings with the medical records and questionnaire data.Ethics and disseminationThe findings will be published in high-ranking journals in the field and presented at national and international conferences.Trial registration numberNCT13560263.

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Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues

Cited by 34 publications

References 67 publications

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Epigenetic age provides insight into tissue origin in endometriosis

Protocol for a longitudinal, prospective cohort study investigating the biology of uterine fibroids and endometriosis, and patients’ quality of life: the FENOX study

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