title: The influence of menstrual cycle and endometriosis on endometrial methylome.
abstract: BACKGROUND
  Alterations in endometrial DNA methylation profile have been proposed as one potential mechanism initiating the development of endometriosis. However, the normal endometrial methylome is influenced by the cyclic hormonal changes, and the menstrual cycle phase-dependent epigenetic signature should be considered when studying endometrial disorders. So far, no studies have been performed to evaluate the menstrual cycle influences and endometriosis-specific endometrial methylation pattern at the same time.
  
  
  RESULTS
  Infinium HumanMethylation 450K BeadChip arrays were used to explore DNA methylation profiles of endometrial tissues from various menstrual cycle phases from 31 patients with endometriosis and 24 healthy women. The DNA methylation profile of patients and controls was highly similar and only 28 differentially methylated regions (DMRs) between patients and controls were found. However, the overall magnitude of the methylation differences between patients and controls was rather small (Δβ ranging from -0.01 to -0.16 and from 0.01 to 0.08, respectively, for hypo- and hypermethylated CpGs). Unsupervised hierarchical clustering of the methylation data divided endometrial samples based on the menstrual cycle phase rather than diseased/non-diseased status. Further analysis revealed a number of menstrual cycle phase-specific epigenetic changes with largest changes occurring during the late-secretory and menstrual phases when substantial rearrangements of endometrial tissue take place. Comparison of cycle phase- and endometriosis-specific methylation profile changes revealed that 13 out of 28 endometriosis-specific DMRs were present in both datasets.
  
  
  CONCLUSIONS
  The results of our study accentuate the importance of considering normal cyclic epigenetic changes in studies investigating endometrium-related disease-specific methylation patterns.
authors.affiliation: Competence Centre on Health Technologies Tartu, Tartu, Estonia.|Tartu University Women's Clinic, Tartu, Estonia.|Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Merli
authors.initials: M
authors.lastname: Saare
authors.affiliation: Institute of Computer Science, University of Tartu, Tartu, Estonia.
authors.forename: Vijayachitra
authors.initials: V
authors.lastname: Modhukur
authors.affiliation: Competence Centre on Health Technologies Tartu, Tartu, Estonia.
authors.forename: Marina
authors.initials: M
authors.lastname: Suhorutshenko
authors.affiliation: Institute of Computer Science, University of Tartu, Tartu, Estonia.
authors.forename: Balaji
authors.initials: B
authors.lastname: Rajashekar
authors.affiliation: Competence Centre on Health Technologies Tartu, Tartu, Estonia.|Tartu University Women's Clinic, Tartu, Estonia.
authors.forename: Kadri
authors.initials: K
authors.lastname: Rekker
authors.affiliation: Competence Centre on Health Technologies Tartu, Tartu, Estonia.|Tartu University Women's Clinic, Tartu, Estonia.|Elite Clinic, Tartu, Estonia.|Women's Clinic, Tartu University Hospital, Tartu, Estonia.
authors.forename: Deniss
authors.initials: D
authors.lastname: Sõritsa
authors.affiliation: Tartu University Women's Clinic, Tartu, Estonia.|Women's Clinic, Tartu University Hospital, Tartu, Estonia.
authors.forename: Helle
authors.initials: H
authors.lastname: Karro
authors.affiliation: Women's Clinic, Tartu University Hospital, Tartu, Estonia.
authors.forename: Pille
authors.initials: P
authors.lastname: Soplepmann
authors.affiliation: Elite Clinic, Tartu, Estonia.
authors.forename: Andrei
authors.initials: A
authors.lastname: Sõritsa
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Rahmioglu
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drong
authors.affiliation: Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Becker
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK.
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.affiliation: Competence Centre on Health Technologies Tartu, Tartu, Estonia.|Tartu University Women's Clinic, Tartu, Estonia.|Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Salumets
authors.affiliation: Competence Centre on Health Technologies Tartu, Tartu, Estonia.|Tartu University Women's Clinic, Tartu, Estonia.
authors.forename: Maire
authors.initials: M
authors.lastname: Peters
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism*; D004717:Endometrium / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008597:Menstrual Cycle / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis
keywords: DNA methylation; Endometriosis; Endometrium; Epigenetics; Illumina 450K; Menstrual cycle; Microarray