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Mamillapalli R, Slutzky R, Mangla A, Gawde N, Taylor HS. Effect of endometriosis-linked microRNAs on hepatic gene expression. F&S SCIENCE 2025; 6:221-231. [PMID: 39971156 DOI: 10.1016/j.xfss.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
OBJECTIVE To determine if microRNAs that are altered in the circulation of women with endometriosis affect metabolic gene expression in hepatic cells. DESIGN In vitro study. SUBJECTS Deidentified tissue from women with endometriosis. EXPOSURE MicroRNAs were used to induce or suppress target genes in hepatic cells. MAIN OUTCOME MEASURES Effect of the microRNAs that are aberrantly expressed in endometriosis on hepatic cell gene expression using quantitative polymerase chain reaction. RESULTS Prior microarray studies on the serum of women with endometriosis showed differential expression of microRNAs miR-Let-7b, miR-125b-5p, miR-150-5p, and miR-3613-5p. Bioinformatic analyses revealed that these microRNAs have predicted binding sites in multiple genes involved in liver metabolism. Transfection of these miRs in HepG2 cells followed by real-time quantitative polymerase chain reaction showed that miR-Let-7b mimic increased the expression of Igfbp1 by 8-fold and reduced the expression of Mrc1 by 3.2-fold, whereas its inhibitor reduced Igfbp1 by 2.8-fold and increased Mrc1 by 5.2-fold. MiR-3613-5p mimic reduced the expression of Cyp2r1 by 2.2-fold and Mrc1 by 4-fold. MiR-125b-5p mimic increased the expression of Fabp4 by 4.1-fold, whereas miR-150-5p mimic increased the expression of Mrc1 by 1.8-fold and Cyp2r1 by 2.5-fold. Inhibitors of both miR-125b-5p and miR-150-5p did not show any effect on any of the genes. CONCLUSION Circulating microRNAs, known to be aberrant in endometriosis-regulated hepatic gene expression, likely contribute to the metabolic defects seen in this disease. Treatment with miR-Let-7b and miR-3613-5p, which are downregulated in endometriosis, reversed the effect of endometriosis on the expression of IGFBP1, MRC1, and CYP2r1 genes. Therefore, miR-Let-7b and miR-3613-5p may be novel candidate therapies for endometriosis, potentially correcting the metabolic changes seen in patients with endometriosis.
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Affiliation(s)
- Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
| | - Rebecca Slutzky
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Anjali Mangla
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Nimisha Gawde
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
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Thong LY, McRae AF, Sirota M, Giudice L, Montgomery GW, Mortlock S. Methylation Risk Score Modelling in Endometriosis: Evidence for Non-Genetic DNA Methylation Effects in a Case-Control Study. Int J Mol Sci 2025; 26:3760. [PMID: 40332393 PMCID: PMC12027649 DOI: 10.3390/ijms26083760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
Endometriosis is a chronic gynaecological disease characterised by endometrial-like tissue found external to the uterus. While several studies have reported strong evidence of a genetic contribution to the disease, studies on the environmental impact on endometriosis are limited. DNA methylation (DNAm) can be influenced by genetic and environmental factors and serves as a useful biological marker of the effects of genetic and environmental exposures on complex diseases. This study aims to develop a methylation risk score (MRS) for endometriosis to increase the power to detect DNAm signals associated with the disease and enhance our understanding of the pathogenesis of the disease. Endometrial methylation and genotype data from 318 controls and 590 cases were analysed. MRSs were developed using several different models. MRS performances were evaluated by splitting samples into training and test sets based on independent cohort institutions, and the area under the receiver-operator curve (AUC) was calculated. The maximum AUC obtained from the best-performing MRS is 0.6748, derived from 746 DNAm sites. The classification performance of MRS and polygenic risk score (PRS) combined was consistently higher than PRS alone. This study demonstrates that there are DNAm signals independent of common genetic variants associated with endometriosis.
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Affiliation(s)
- Li Ying Thong
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; (L.Y.T.); (A.F.M.); (G.W.M.)
| | - Allan F. McRae
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; (L.Y.T.); (A.F.M.); (G.W.M.)
| | - Marina Sirota
- Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA 94158, USA;
- Department of Pediatrics, Division of Neonatology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Linda Giudice
- Center for Reproductive Sciences, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA;
| | - Grant W. Montgomery
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; (L.Y.T.); (A.F.M.); (G.W.M.)
| | - Sally Mortlock
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; (L.Y.T.); (A.F.M.); (G.W.M.)
- Australian Women and Girls’ Health Research Centre, University of Queensland, Brisbane, QLD 4006, Australia
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Ducreux B, Patrat C, Firmin J, Ferreux L, Chapron C, Marcellin L, Parpex G, Bourdon M, Vaiman D, Santulli P, Fauque P. Systematic review on the DNA methylation role in endometriosis: current evidence and perspectives. Clin Epigenetics 2025; 17:32. [PMID: 39985111 PMCID: PMC11846336 DOI: 10.1186/s13148-025-01828-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/30/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Endometriosis appears to have a multilayered etiology, with genetic and epigenetic factors each contributing half of the pathogenesis. The molecular processes that underlie the onset of endometriosis are yet unclear, but it is assumed that an important contributor in the etiopathology of the disease is DNA methylation. METHODS We conducted a systematic review of the literature regarding DNA methylation in endometriosis following PRISMA guidelines. Records were obtained from PubMed and Web of Science on May 31, 2024. Original research articles analyzing regional or genome-wide DNA methylation in patients with confirmed endometriosis (by surgery and/or histological examination) were given consideration for inclusion. Only human studies were included, and there were no restrictions on the types of tissue that was analyzed (i.e., endometrium, blood, or fetal tissue). The study selection process was run by two manual reviewers. In parallel, an adapted virtual artificial intelligence-powered reviewer operated study selection and results were compared with the manual reviewers' selection. Studies were divided into targeted (e.g., single gene or region level) and epigenome-wide association studies. For each, we extracted a list of genes studied with precise location of CpGs analyzed and the DNA methylation status according to the groups compared. Quality assessment of studies was performed following the Newcastle-Ottawa scale. Quality of evidence was graded following the Grading of Recommendations Assessment, Development and Evaluation. RESULTS A total of 955 studies were screened, and 70 were identified as relevant for systematic review. Our analyses displayed that endometriosis could be polyepigenetic and with alterations in specific genes implicated in major signaling pathways contributing to the disease etiopathology (cell proliferation, differentiation, and division [PI3K-Akt and Wnt-signaling pathway], cell division [MAPK pathway], cell adhesion, cell communication, developmental processes, response to hormone, apoptosis, immunity, neurogenesis, and cancer). CONCLUSION Our systematic review indicates that endometriosis is associated with DNA methylation modifications at specific genes involved in key endometrial biological processes, particularly in the ectopic endometrium. As DNA methylation appears to be an integral component of the pathogenesis of endometriosis, the identification of DNA methylation biomarkers would likely help better understand its causes and aggravating factors as well as potentially facilitate its diagnosis and support the development of new therapeutic approaches.
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Affiliation(s)
- Bastien Ducreux
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Centre Hospitalier Universitaire (CHU), Faculty of Medicine, INSERM 1231, Université de Bourgogne-Europe, Dijon, France
| | - Catherine Patrat
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Julie Firmin
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Lucile Ferreux
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Charles Chapron
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Louis Marcellin
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Guillaume Parpex
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Mathilde Bourdon
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Daniel Vaiman
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
| | - Pietro Santulli
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France
- Department of Gynecology-Obstetric and Assisted Reproduction, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France
| | - Patricia Fauque
- Faculty of Medicine, Inserm U1016, Université de Paris Cité, 75014, Paris, France.
- Department of Reproductive Biology-CECOS, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, 75014, Paris, France.
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Văduva CC, Dîră L, Boldeanu L, Șerbănescu MS, Carp-Velișcu A. A Narrative Review Regarding Implication of Ovarian Endometriomas in Infertility. Life (Basel) 2025; 15:161. [PMID: 40003570 PMCID: PMC11856244 DOI: 10.3390/life15020161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/18/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Endometriosis is a multifaceted gynecological disorder defined by endometrium-like tissue outside the uterine cavity. It is mainly localized in the pelvis and creates a local inflammatory environment responsible for its manifestations and complications. In 30-50% of cases, endometriosis is associated with infertility. In 17-44% of cases, the ovaries are affected in the form of ovarian endometriomas (OEs). The symptoms of OEs are not very pronounced. The development is slow. Diagnosis is difficult because OEs resemble cystic ovarian pathology, which is so diverse. The actual diagnosis is possible through direct visualization or laparoscopy. Surgical treatment by cystectomy is common for OEs. Recently, other therapeutic modalities have emerged that have less impact on ovarian reserves and pregnancy rates. In this context, the review attempts to shed light on the best diagnostic and treatment methods for an insidious pathology with a major impact on fertility.
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Affiliation(s)
- Constantin-Cristian Văduva
- Department of Obstetrics and Gynecology, University of Medicine and Pharmacy, Filantropia Clinical Municipal Hospital Craiova, 200143 Craiova, Romania; (C.-C.V.); (L.D.)
- Department of Obstetrics, Gynecology and IVF, HitMed Medical Center, 200130 Craiova, Romania
| | - Laurențiu Dîră
- Department of Obstetrics and Gynecology, University of Medicine and Pharmacy, Filantropia Clinical Municipal Hospital Craiova, 200143 Craiova, Romania; (C.-C.V.); (L.D.)
- Department of Obstetrics, Gynecology and IVF, HitMed Medical Center, 200130 Craiova, Romania
| | - Lidia Boldeanu
- Department of Microbiology, University of Medicine and Pharmacy, County Clinical Emergency Hospital, 200642 Craiova, Romania;
| | - Mircea-Sebastian Șerbănescu
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy, 200349 Craiova, Romania
- Department of Pathology, Filantropia Clinical Municipal Hospital Craiova, 200143 Craiova, Romania
| | - Andreea Carp-Velișcu
- Department of Obstetrics, Gynecology and IVF, “Carol Davila” Bucharest Medical University, Prof. Dr. “Panait Sarbu” Clinical Hospital, 060251 Bucharest, Romania;
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Hu Y, Chen H, Jin L, Chi X, Zhao J, Cao Q. Hypomethylation of IL6ST promotes development of endometriosis by activating JAK2/STAT3 signaling pathway. PLoS One 2025; 20:e0317569. [PMID: 39821173 PMCID: PMC11737718 DOI: 10.1371/journal.pone.0317569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/30/2024] [Indexed: 01/30/2025] Open
Abstract
Endometriosis is a chronic inflammatory disorder characterized by presence of endometrial tissue outside the uterine cavity. Immunohistochemical analysis (IHC) revealed markedly elevated expression of IL6ST in endometrial tissue of patients with ovarian endometriosis. Level of methylation of IL6ST is diminished in patients with endometriosis, whereas level of mRNA expression is markedly elevated by RT-PCR. Cell Counting Kit-8, Transwell, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays substantiated endometrial stromal cells stably transfected with 3*FLAG-IL6ST plasmid exhibited enhanced viability, augmented invasive capacity, and notable reduction in apoptosis rates. Furthermore, IL6ST facilitated progression of endometriosis by activating mitogen-activated protein kinase 9/Signal Transducer and Activator of Transcription 3 signaling pathway. Western blot analysis revealed significantly elevated protein levels of p-JAK2/JAK2, p-STAT3/STAT3, HIF-1α, and VEGF in IL6ST overexpression group. Conversely, JAK2/STAT3 inhibitor WP1066 had markedly reduced p-JAK2 and p-STAT3 protein levels in IL6ST overexpression group. Inhibiting JAK2/STAT3 signaling pathway had mitigating effect on proliferative and invasive enhancement of endometrial stromal cells, as well as inhibition of apoptosis induced by IL6ST. These findings offer novel potential targets and strategies for the treatment of endometriosis.
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Affiliation(s)
- Yue Hu
- Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China
- Department of Gynecology, Shijiazhuang People’s Hospital, Shijiazhuang, Hebei, People’s Republic of China
| | - Hailong Chen
- Department of Gynecology, Shijiazhuang People’s Hospital, Shijiazhuang, Hebei, People’s Republic of China
| | - Lijuan Jin
- Department of Gynecology, Shijiazhuang People’s Hospital, Shijiazhuang, Hebei, People’s Republic of China
| | - Xiumei Chi
- Department of Gynecology, Shijiazhuang People’s Hospital, Shijiazhuang, Hebei, People’s Republic of China
| | - Jian Zhao
- Department of Gynecology, Shijiazhuang People’s Hospital, Shijiazhuang, Hebei, People’s Republic of China
| | - Qinying Cao
- Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China
- Department of Gynecology, Shijiazhuang People’s Hospital, Shijiazhuang, Hebei, People’s Republic of China
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Kobayashi H, Imanaka S, Yoshimoto C, Matsubara S, Shigetomi H. Rethinking the pathogenesis of endometriosis: Complex interactions of genomic, epigenetic, and environmental factors. J Obstet Gynaecol Res 2024; 50:1771-1784. [PMID: 39293995 DOI: 10.1111/jog.16089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 09/01/2024] [Indexed: 09/20/2024]
Abstract
AIM Endometriosis is a complex, multifactorial disease. Recent advances in molecular biology underscore that somatic mutations within the epithelial component of the normal endometrium, alongside aberrant epigenetic alterations within endometrial stromal cells, may serve as stimulators for the proliferation of endometriotic tissue within the peritoneal cavity. Nevertheless, pivotal inquiries persist: the deterministic factors driving endometriosis development in certain women while sparing others, notwithstanding comparable experiences of retrograde menstruation. Within this review, we endeavor to synopsize the current understanding of diverse pathophysiologic mechanisms underlying the initiation and progression of endometriosis and delineate avenues for future research. METHODS A literature search without time restriction was conducted utilizing PubMed and Google Scholar. RESULTS Given that aberrant clonal expansion stemming from cancer-associated mutations is common in normal endometrial tissue, only endometrial cells harboring mutations imparting proliferative advantages may be selected for survival outside the uterus. Endometriotic cells capable of engendering metabolic plasticity and modulating mitochondrial dynamics, thereby orchestrating responses to hypoxia, oxidative stress, inflammation, hormonal stimuli, and immune surveillance, and adeptly acclimating to their harsh surroundings, stand a chance at viability. CONCLUSION The genesis of endometriosis appears to reflect the evolutionary principles of mutation, selection, clonal expansion, and adaptation to the environment.
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Affiliation(s)
- Hiroshi Kobayashi
- Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara, Japan
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
| | - Shogo Imanaka
- Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara, Japan
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
| | - Chiharu Yoshimoto
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
- Department of Obstetrics and Gynecology, Nara Prefecture General Medical Center, Nara, Japan
| | - Sho Matsubara
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
- Department of Medicine, Kei Oushin Clinic, Nishinomiya, Japan
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan
- Department of Gynecology and Reproductive Medicine, Aska Ladies Clinic, Nara, Japan
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Kina BG, Topbas Selcuki NF, Bahat PY, Usta T, Aydin S, Rahmioglu N, Tuncer FN, Oral E. Whole exome sequencing reveals novel candidate variants for endometriosis utilizing multiple affected members in a single family. Mol Genet Genomic Med 2024; 12:e2312. [PMID: 38013616 PMCID: PMC10767589 DOI: 10.1002/mgg3.2312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/25/2023] [Accepted: 10/13/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Endometriosis is an estrogen-dependent, chronic inflammatory disease that affects 10% of women during the reproductive ages. Despite the estimated 50% heritability for the condition, only 26% was associated with common genetic variants. Thus, necessity of identifying rare variants for the missing heritability is implicated in the literature. Therefore, our study aimed to identify novel rare genetic variants involved in the pathogenesis of endometriosis utilizing a family of multiple affected members. METHODS A family composed of four affected women along with their two unaffected mothers were recruited at a single gynecology and infertility clinic specialized in endometriosis. All patients presented with endometriomas, which was visualized by transvaginal ultrasonography. Two affected individuals had received laparoscopic endometrioma excision and therefore were diagnosed with recurrent disease. One mother had a history of endometrial serous adenocarcinoma (ESC) for which she underwent hysterectomy with bilateral oophorectomy. Three endometriosis cases were whole exome sequenced on Illumina NextSeq 550 platform with an average of 90% coverage. Candidate genes were confirmed by Sanger sequencing and followed-up with family segregation. RESULTS Novel rare variants were identified in TNFRSF1B (NM_001066.3: c.1072G>A, p.(Ala358Thr)) and GEN1 (NM_001130009.3: c.1574C>T, p.(Ser525Leu)) as possible genetic causes of endometriosis. A third novel rare variant was identified in CRABP1 (NM_004378.3:c.54G>C, p.(Glu18Asp)) only on the mother with ESC history and her daughters. CONCLUSION Novel candidate genetic variants that might contribute to endometriosis were suggested that need replication through independent cohorts or validation by functional studies. The family has also received genetic counseling and that the affected daughters are on clinical follow-up, accordingly.
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Affiliation(s)
- Busra Gizem Kina
- Department of Genetics, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityIstanbulTurkey
- Graduate School of Health SciencesIstanbul UniversityIstanbulTurkey
| | - Nura Fitnat Topbas Selcuki
- Department of Obstetrics and Gynecology, Istanbul Sisli Hamidiye Etfal Training and Research HospitalUniversity of Health Sciences TurkiyeIstanbulTurkey
| | - Pinar Yalcin Bahat
- Department of Obstetrics and Gynecology, Istanbul Kanuni Sultan Suleyman Training and Research HospitalUniversity of Health Sciences TurkiyeIstanbulTurkey
| | - Taner Usta
- Department of Obstetrics and Gynecology, Acibadem Altunizade HospitalMehmet Ali Aydinlar UniversityIstanbulTurkey
| | - Sevcan Aydin
- Department of Genetics, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityIstanbulTurkey
- Graduate School of Health SciencesIstanbul UniversityIstanbulTurkey
| | - Nilufer Rahmioglu
- Oxford Endometriosis Care Centre, Nuffield Department of Women's and Reproductive HealthUniversity of Oxford, Women's Centre, John Radcliffe HospitalOxfordUK
- Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Feyza Nur Tuncer
- Department of Genetics, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityIstanbulTurkey
| | - Engin Oral
- Department of Obstetrics and GynecologyBezmialem Vakif UniversityIstanbulTurkey
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Colón-Caraballo M, Flores-Caldera I. Translational aspects of the endometriosis epigenome. EPIGENETICS IN HUMAN DISEASE 2024:883-929. [DOI: 10.1016/b978-0-443-21863-7.00008-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Bedrick BS, Courtright L, Zhang J, Snow M, Amendola ILS, Nylander E, Cayton-Vaught K, Segars J, Singh B. A Systematic Review of Epigenetics of Endometriosis. F&S REVIEWS 2024; 5:100070. [PMID: 38524912 PMCID: PMC10956470 DOI: 10.1016/j.xfnr.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2024]
Abstract
Objective To assess the current literature evaluating the epigenetics of endometriosis in humans. Evidence Review A systematic review was conducted in accordance with the PRISMA guidelines within PubMed, EBSCOhost, Cochrane Library, Embase, Scopus, and Web of Science Core Collection. A comprehensive search strategy was developed by a data informationist. Observational and interventional studies assessing epigenetics in humans published in English up to January 15th, 2023, were included. Two reviewers independently screened studies evaluating the role of epigenetics in endometriosis. The risk of bias was assessed using Cochrane RoB 2.0 tool and the Newcastle-Ottawa scale. Extracted data were analyzed descriptively. Results We identified 18.639 studies, of which 57 were included, comprising 1.623 patients with endometriosis and 1.243 controls. Among the 57 studies included, 50 (88%) were case-control studies, and 7 (12%) were cross-sectional. Fifty-nine percent of the studies were Asian, 25% were from America, 14% were European, and 2% were from Africa. Acetylation and methylation were the two main key histone modifications that were centered in this review. Accordingly, we classified the studies as those focusing on genome-wide methylation and those on histone acetylation. Several studies identified an association between endometriosis and hypermethylated genes, including the PGR-B, SF-1, and RASSF1A. The genes HOXA10, COX-2, IL-12B, and GATA6 were found to be hypomethylated in endometriotic tissue by several studies. In regards to histone modification, multiple studies reported that the acetylation levels of histones H3 and H4 affect multiple genes associated with endometriosis. In addition, HDAC2 was found to be elevated in endometriosis patients in two studies. Conclusion Several studies reported a significant difference between specific genes' methylation levels in endometrial biopsies and normal tissue, which suggests that DNA methylation may play an important role in the modulation of the genotype in endometriotic tissue. Acetylation and methylation are the two key histone modifications leading to differential gene expression in endometriotic tissues. The alterations in gene expression reported by the 57 studies can have direct implications on cell cycle growth, cell cycle arrest, and apoptosis and, therefore, might play a key role in the pathogenesis of endometriosis. This review offers insight that histone modifications need further research to evaluate their role as potential biomarkers and treatment targets for endometriosis. Although several key similarities were reported, there were some disagreements among the results, which might be attributable to the heterogeneity between studies. Further research with a more robust standardization is needed to validate the epigenetic changes in endometriosis.
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Affiliation(s)
- Bronwyn S. Bedrick
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura Courtright
- Division of Reproductive Sciences & Women’s Health Research, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jiahui Zhang
- Department of Obstetrics & Gynecology, University of Vermont Medical Center, Burlington, VT, USA
| | - Morgan Snow
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Isabela Landsteiner Sampaio Amendola
- Division of Reproductive Sciences & Women’s Health Research, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elisabeth Nylander
- Informationist Services, Welch Medical Library, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kamaria Cayton-Vaught
- Division of Reproductive Sciences & Women’s Health Research, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James Segars
- Division of Reproductive Sciences & Women’s Health Research, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Bhuchitra Singh
- Division of Reproductive Sciences & Women’s Health Research, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Delli Carpini G, Giannella L, Di Giuseppe J, Montik N, Montanari M, Fichera M, Crescenzi D, Marzocchini C, Meccariello ML, Di Biase D, Vignini A, Ciavattini A. Homozygous C677T Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism as a Risk Factor for Endometriosis: A Retrospective Case-Control Study. Int J Mol Sci 2023; 24:15404. [PMID: 37895084 PMCID: PMC10607746 DOI: 10.3390/ijms242015404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
This study was conducted to evaluate the role of methylenetetrahydrofolate reductase (MTHFR) C677T homozygous polymorphism as a risk factor for endometriosis. A retrospective case-control study was conducted from January 2020 to December 2022 on all patients attending the gynecological outpatient clinic of our institution who had performed an MTHFR polymorphisms test. Patients with endometriosis were considered cases, while those without endometriosis were considered controls. The presence of an MTHFR C677T homozygous polymorphism was defined as exposure. Risk factors for endometriosis were considered confounders in a binomial logistic regression, with endometriosis diagnosis as the dependent variable. Among the 409 included patients, 106 (25.9%) cases and 303 (74.1%) controls were identified. A higher rate of MTHFR C677T homozygous polymorphism was found in patients with endometriosis (24.5% vs. 15.8%, p = 0.0453), with an adOR of 1.889 (95% CI 1.076-3.318, p = 0.0269) at the binomial logistic regression. A history of no previous pregnancy was associated with an endometriosis diagnosis (adOR 2.191, 95% CI 1.295-3.708, p = 0.0035). An MTHFR C677T homozygous polymorphism could be considered a risk factor for endometriosis. Epigenetic modifications may be the most important mechanism explaining the observed association through the processes of altered DNA methylation and reduced activity of antioxidant systems.
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Affiliation(s)
- Giovanni Delli Carpini
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Luca Giannella
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Jacopo Di Giuseppe
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Nina Montik
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Michele Montanari
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Mariasole Fichera
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Daniele Crescenzi
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Carolina Marzocchini
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Maria Liberata Meccariello
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Donato Di Biase
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
| | - Arianna Vignini
- Section of Biochemistry, Biology and Physics, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy;
| | - Andrea Ciavattini
- Gynecologic Section, Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, 60213 Ancona, Italy; (G.D.C.); (L.G.); (J.D.G.); (N.M.); (M.M.); (M.F.); (D.C.); (C.M.); (M.L.M.); (D.D.B.)
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Lei L, Xu X, Gong C, Lin B, Li F. Integrated analysis of genome-wide gene expression and DNA methylation profiles reveals candidate genes in ovary endometriosis. Front Endocrinol (Lausanne) 2023; 14:1093683. [PMID: 37033258 PMCID: PMC10076879 DOI: 10.3389/fendo.2023.1093683] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 03/10/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND The incidence of endometriosis (EMs), a common disease in gynecology, has increased over the years. Women suffer from the symptoms caused by EMs, such as chronic pelvic pain, dysmenorrhea, and infertility. However, the etiology and pathophysiology of EMs remain unclear. This study aimed to identify candidate genes of endometriosis through integrated analysis of genome-wide gene expression and DNA methylation profiles. RESULTS Eutopic and ectopic endometrial tissues were collected from patients who were diagnosed as ovarian EMs. Genome-wide methylation profiling identified 17551 differentially methylated loci, with 9777 hypermethylated and 7774 hypomethylated loci. Differentially methylated loci were mainly concentrated in the gene body and intergenic regions. Genome-wide gene expression profiling identified 1837 differentially expressed genes (DEGs), with 1079 genes upregulated and 758 downregulated in ectopic groups. Integrated analysis revealed that DNA methylation was negatively correlated to gene expression in most genomic regions, such as exon, 3'UTR, 5'UTR, and promoter. We also identified promoter-related (53 downregulated and 113 upregulated) and enhancer-related DMGs (212 downregulated and 232 upregulated), which were significantly correlated to the gene expression. Further validation of the top-ranked genes belonging to differentially methylated genes (DMGs) and DEGs revealed that TMEM184A, GREM2, SFN, KIR3DX1, HPGD, ESR1, BST2, PIK3CG and RNASE1 were significant candidate genes in ovarian endometriosis. CONCLUSION Our study revealed the significance of DNA methylation in the gene expression in ovary endometriosis, which provides new insights and a molecular foundation for understanding the underlying mechanisms of endometriosis.
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Affiliation(s)
- Lei Lei
- Department of Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinxin Xu
- Department of Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chengchen Gong
- Department of Dermatology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bowen Lin
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Fang Li, ; Bowen Lin,
| | - Fang Li
- Department of Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Fang Li, ; Bowen Lin,
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Deryabin PI, Borodkina AV. Epigenetic clocks provide clues to the mystery of uterine ageing. Hum Reprod Update 2022; 29:259-271. [PMID: 36515535 DOI: 10.1093/humupd/dmac042] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Rising maternal ages and age-related fertility decline are a global challenge for modern reproductive medicine. Clinicians and researchers pay specific attention to ovarian ageing and hormonal insufficiency in this regard. However, uterine ageing is often left out of the picture, with the majority of reproductive clinicians being close to unanimous on the absence of age-related functional decline in the uterine tissues. Therefore, most existing techniques to treat an age-related decline in implantation rates are based primarily on hormonal supplementation and oocyte donation. Solving the issue of uterine ageing might lead to an adjustment to these methods. OBJECTIVE AND RATIONALE A focus on uterine ageing and the possibility of slowing it emerged with the development of the information theory of ageing, which identifies genomic instability and erosion of the epigenetic landscape as important drivers of age-related decline in the functionality of most cells and tissues. Age-related smoothing of this landscape and a decline in tissue function can be assessed by measuring the ticking of epigenetic clocks. Within this review, we explore whether the uterus experiences age-related alterations using this elegant approach. We analyse existing data on epigenetic clocks in the endometrium, highlight approaches to improve the accuracy of the clocks in this cycling tissue, speculate on the endometrial pathologies whose progression might be predicted by the altered speed of epigenetic clocks and discuss the possibilities of slowing down the ticking of these clocks. SEARCH METHODS Data for this review were identified by searches of Medline, PubMed and Google Scholar. References from relevant articles using the search terms 'ageing', 'maternal age', 'female reproduction', 'uterus', 'endometrium', 'implantation', 'decidualization', 'epigenetic clock', 'biological age', 'DNA methylation', 'fertility' and 'infertility' were selected. A total of 95 articles published in English between 1985 and 2022 were included, six of which describe the use of the epigenetic clock to evaluate uterine/endometrium ageing. OUTCOMES Application of the Horvath and DNAm PhenoAge epigenetic clocks demonstrated a poor correlation with chronological age in the endometrium. Several approaches were suggested to enhance the predictive power of epigenetic clocks for the endometrium. The first was to increase the number of samples in the training dataset, as for the Zang clock, or to use more sophisticated clock-building algorithms, as for the AltumAge clock. The second method is to adjust the clocks according to the dynamic nature of the endometrium. Using either approach revealed a strong correlation with chronological age in the endometrium, providing solid evidence for age-related functional decline in this tissue. Furthermore, age acceleration/deceleration, as estimated by epigenetic clocks, might be a promising tool to predict or to gain insights into the origin of various endometrial pathologies, including recurrent implantation failure, cancer and endometriosis. Finally, there are several strategies to slow down or even reverse epigenetic clocks that might be applied to reduce the risk of age-related uterine impairments. WIDER IMPLICATIONS The uterine factor should be considered, along with ovarian issues, to correct for the decline in female fertility with age. Epigenetic clocks can be tested to gain a deeper understanding of various endometrial disorders.
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Affiliation(s)
- Pavel I Deryabin
- Mechanisms of Cellular Senescence Group, Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia
| | - Aleksandra V Borodkina
- Mechanisms of Cellular Senescence Group, Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia
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Yahaya TO, Bashar DM, Oladele EO, Umar J, Anyebe D, Izuafa A. Epigenetics in the etiology and management of infertility. World J Med Genet 2022; 10:7-21. [DOI: 10.5496/wjmg.v10.i2.7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/28/2022] [Accepted: 10/12/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Epigenetic disruptions have been implicated in some cases of infertility and can serve as therapeutic targets. However, the involvement of epigenetics in infertility has not received adequate attention.
AIM This study aimed to determine the epigenetic basis of infertility in order to enhance public knowledge.
METHODS Relevant articles on the subject were collected from PubMed, RCA, Google Scholar, SpringerLink, and Scopus. The articles were pooled together and duplicates were removed using Endnote software.
RESULTS Available information shows that epigenetic mechanisms, mainly DNA methylation, histone modification, and microRNA interference are necessary for normal gametogenesis and embryogenesis. As a result, epigenetic disruptions in genes that control gametogenesis and embryogenesis, such as DDX3X, ADH4, AZF, PLAG1, D1RAS3, CYGB, MEST, JMJD1A, KCNQ1, IGF2, H19, and MTHFR may result in infertility. Aberrant DNA methylation during genomic imprinting and parental epigenetic mark erasures, in particular, may affect the DNA epigenomes of sperm and oocytes, resulting in reproductive abnormalities. Histone epigenetic dysregulation during oocyte development and histone-protamine replacement in the sperm may also cause reproductive abnormalities. Furthermore, overexpression or repression of certain microRNAs embedded in the ovary, testis, embryo, as well as granulosa cells and oocytes may impair reproduction. Male infertility is characterized by spermatogenesis failure, which includes oligozoospermia, asthenozoospermia, and teratozoospermia, while female infertility is characterized by polycystic ovary syndrome. Some epigenetic modifications can be reversed by deactivating the regulatory enzymes, implying that epigenetic reprogramming could help treat infertility in some cases. For some disorders, epigenetic drugs are available, but none have been formulated for infertility.
CONCLUSION Some cases of infertility have an epigenetic etiology and can be treated by reversing the same epigenetic mechanism that caused it. As a result, medical practitioners are urged to come up with epigenetic treatments for infertility that have an epigenetic cause.
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Affiliation(s)
| | - Danlami M Bashar
- Department of Microbiology, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Esther O Oladele
- Biology Unit, Distance Learning Institute, University of Lagos, Lagos State 23401, Nigeria
| | - Ja'afar Umar
- Department of Biological Sciences, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Daniel Anyebe
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Abdulrazaq Izuafa
- Department of Biological Sciences, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
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Bonavina G, Taylor HS. Endometriosis-associated infertility: From pathophysiology to tailored treatment. Front Endocrinol (Lausanne) 2022; 13:1020827. [PMID: 36387918 PMCID: PMC9643365 DOI: 10.3389/fendo.2022.1020827] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/06/2022] [Indexed: 11/13/2022] Open
Abstract
Despite the clinically recognized association between endometriosis and infertility, the mechanisms implicated in endometriosis-associated infertility are not fully understood. Endometriosis is a multifactorial and systemic disease that has pleiotropic direct and indirect effects on reproduction. A complex interaction between endometriosis subtype, pain, inflammation, altered pelvic anatomy, adhesions, disrupted ovarian reserve/function, and compromised endometrial receptivity as well as systemic effects of the disease define endometriosis-associated infertility. The population of infertile women with endometriosis is heterogeneous, and diverse patients' phenotypes can be observed in the clinical setting, thus making difficult to establish a precise diagnosis and a single mechanism of endometriosis related infertility. Moreover, clinical management of infertility associated with endometriosis can be challenging due to this heterogeneity. Innovative non-invasive diagnostic tools are on the horizon that may allow us to target the specific dysfunctional alteration in the reproduction process. Currently the treatment should be individualized according to the clinical situation and to the suspected level of impairment. Here we review the etiology of endometriosis related infertility as well as current treatment options, including the roles of surgery and assisted reproductive technologies.
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Affiliation(s)
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States
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15
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Milesi MM, Lorenz V, Varayoud J. Aberrant Hoxa10 gene methylation as a mechanism for endosulfan-induced implantation failures in rats. Mol Cell Endocrinol 2022; 547:111576. [PMID: 35114330 DOI: 10.1016/j.mce.2022.111576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 10/19/2022]
Abstract
DNA methylation is a well-established epigenetic mechanism controlling gene expression. Environmental chemicals, such as pesticides have been shown to alter DNA methylation. We have previously shown that the insecticide endosulfan impairs female fertility in rats by increasing the rate of preimplantation embryo losses. In this study, we evaluated whether early postnatal exposure to endosulfan affects long-term transcriptional regulation of Homeobox A10 (Hoxa10) gene, which is a key marker of endometrial receptivity. Female rats were neonatally exposed to 6 or 600 μg/kg/day (ENDO6 and ENDO600, respectively) of endosulfan and uterine samples collected on gestational day (GD) 5. Hoxa10 protein and mRNA levels were assessed by immunohistochemistry and quantitative real-time PCR (qRT-PCR), respectively. In silico analysis of enzyme-specific restriction sites and predicted transcription factors were performed to investigate the methylation status of the regulatory regions of Hoxa10 gene by methylation-sensitive restriction enzymes-PCR technique. The expression of the DNA methyltransferases (Dnmts) was also evaluated. ENDO600 showed a decreased uterine Hoxa10 expression at protein and transcript level, while ENDO6 decreased only the level of transcripts, during the receptive stage. In addition, endosulfan increased levels of Dnmt3a and Dnmt3b. Dysregulation of DNA methylation patterns of Hoxa10 regulatory regions was detected in ENDO6- and ENDO600-treated rats. All these results suggest that aberrant DNA methylation in Hoxa10 gene could be an underlining mechanism contributing to explain endosulfan-induced preimplantation losses.
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Affiliation(s)
- María Mercedes Milesi
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
| | - Virginia Lorenz
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
| | - Jorgelina Varayoud
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina; Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
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Meixell DA, Mamillapalli R, Taylor HS. Methylation of microribonucleic acid Let-7b regulatory regions in endometriosis. F&S SCIENCE 2022; 3:197-203. [PMID: 35560017 DOI: 10.1016/j.xfss.2022.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/17/2022] [Accepted: 03/25/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To evaluate whether Let-7b regulatory regions are methylated in endometriosis and whether there are specific CpG methylation sites that can be identified as key epigenetic regulatory locations. DESIGN Laboratory study. SETTING Academic Medical Center. PATIENT(S) Twenty-one women with (n = 12) and without (n = 9) endometriosis. INTERVENTION(S) Laboratory investigation. In vitro assessment of Let-7b methylation. MAIN OUTCOME MEASURE(S) Four targeted regions upstream of Let-7b predicted to be the regulatory regions of this microribonucleic acid (miRNA) were amplified using bisulfite-specific polymerase chain reaction. Deoxyribonucleic acid sequences were analyzed to determine methylation status at each predicted regulatory region and CpG island. RESULT(S) Regions were chosen on the basis of percent (%) GC content and data from Ensembl/ENCODE databases, which predict locations of promoters, enhancers, CTCF, and transcription factor binding sites as well as candidate cis-regulatory elements. A region 1,161 base pairs upstream of the Let-7b coding region was significantly differentially methylated in ectopic samples compared with eutopic endometrium from patients with endometriosis. Four specific CpG islands within this region 2 were further analyzed individually, and 1 was found to be significantly methylated in endometriosis. We identified that transcription factor SP1 was predicted to bind to a sequence that contained this specific methylated CpG in endometriosis. CONCLUSION(S) We identified differential Let-7b methylation in endometriosis, demonstrating that the epigenetic nature of the disease extends to the regulation of miRNAs. Methylation of this novel Let-7b regulatory region explains the decreased levels of this miRNA in endometriosis and is distinct from the regions implicated in regulating Let-7b in cancer. Understanding of the disease-specific mechanisms leading to diminished expression may allow for better understanding of the etiology of endometriosis as well as development of new treatment options.
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Affiliation(s)
- Dana A Meixell
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
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17
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Li L, Facadio Antero M, Zhang M, Chu T, Seckin T, Ayhan A, Pisanic T, Wang TL, Cope L, Segars J, Shih IM. Mutation and methylation profiles of ectopic and eutopic endometrial tissues. J Pathol 2021; 255:387-398. [PMID: 34396532 PMCID: PMC9808974 DOI: 10.1002/path.5778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 06/27/2021] [Accepted: 08/11/2021] [Indexed: 01/05/2023]
Abstract
Adenomyosis and peritoneal endometriosis are common gynecologic lesions; they are characterized by aberrant locations of normal-appearing endometrium in myometrium and peritoneal surface, respectively. Both ectopic lesions are speculated to originate from uterine eutopic endometrium, which is composed of epithelium and stroma, but how these two different tissue types co-evolve in ectopic locations remains unclear. Here, we analyzed exome-wide mutations and global methylation in microdissected epithelium and stroma separately in paired adenomyosis, peritoneal endometriosis, and endometrium to investigate their relationship. Analyses of somatic mutations and their allele frequencies indicate monoclonal development not only in epithelium but also in the stroma of adenomyosis and peritoneal endometriosis. Our preliminary phylogenetic study suggests a plausible clonal derivation in epithelium and stroma of both ectopic and eutopic endometrium from the same founder epithelium-stroma progenitor cells. While a patient-specific methylation landscape is evident, adenomyosis epithelium and stroma can be distinguished from normal-appearing eutopic endometrium epigenetically. In summary, endometrial stroma, like its epithelial counterpart, could be clonal and both ectopic and eutopic endometrium following divergent evolutionary trajectories. Our data also warrant future investigations into the role of endometrial stroma in the pathobiology of endometrium-related disorders. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Lihong Li
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria Facadio Antero
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ming Zhang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tiffany Chu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tamer Seckin
- Department of Gynecology, Lenox Hill Hospital and Zucker School of Medicine at Hofstra/Northwell, New York, USA
| | - Ayse Ayhan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas Pisanic
- Johns Hopkins Institute of NanoBio Technology, Johns Hopkins University, Baltimore, MD, USA
| | - Tian-Li Wang
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Leslie Cope
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James Segars
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ie-Ming Shih
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,Correspondence to: Ie-Ming Shih, Cancer Research Bldg-2, Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions,
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18
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Mikhaleva LM, Radzinsky VE, Orazov MR, Khovanskaya TN, Sorokina AV, Mikhalev SA, Volkova SV, Shustova VB, Sinelnikov MY. Current Knowledge on Endometriosis Etiology: A Systematic Review of Literature. Int J Womens Health 2021; 13:525-537. [PMID: 34104002 PMCID: PMC8179825 DOI: 10.2147/ijwh.s306135] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/04/2021] [Indexed: 12/30/2022] Open
Abstract
Objective To review the mechanisms of endometriosis development, including those related to epigenetic mutations, cellular dysregulation, inflammatory processes, and oxidative stress. Methods A systematic literature review regarding current aspects of endometriosis etiology, genesis and development was performed using the PubMed, Google Scholar, and eLibrary databases. Keywords included endometriosis, etiology, development, genesis, associations and mechanisms. A multilingual search was performed. Results Several mechanisms underline the pathophysiological pathways for endometriosis development. Epigenetic mutations, external and internal influences, and chronic conditions have a significant impact on endometriosis development, survival and regulation. Several historically valid theories on endometriosis development were discussed, as well as updated findings. Conclusion Despite recent advances, fundamental problems in understanding endometriosis remain unresolved. The identification of unknown circulating epithelial progenitors or stem cells that are responsible for epithelial growth in both the endometrium and endometriotic foci seems to be the next step in solving these questions.
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Affiliation(s)
- Lyudmila M Mikhaleva
- Laboratory of Clinical Morphology, Research Institute of Human Morphology, Moscow, Russia
| | | | | | - Tatyana N Khovanskaya
- Laboratory of Clinical Morphology, Research Institute of Human Morphology, Moscow, Russia
| | - Anastasia V Sorokina
- Laboratory of Clinical Morphology, Research Institute of Human Morphology, Moscow, Russia
| | | | | | - Victoria B Shustova
- Laboratory of Clinical Morphology, Research Institute of Human Morphology, Moscow, Russia
| | - Mikhail Y Sinelnikov
- Laboratory of Clinical Morphology, Research Institute of Human Morphology, Moscow, Russia
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Joshi NR, Kohan-Ghadr HR, Roqueiro DS, Yoo JY, Fru K, Hestermann E, Yuan L, Ho SM, Jeong JW, Young SL, Lessey BA, Fazleabas AT. Genetic and epigenetic changes in the eutopic endometrium of women with endometriosis: association with decreased endometrial αvβ3 integrin expression. Mol Hum Reprod 2021; 27:6163298. [PMID: 33693877 DOI: 10.1093/molehr/gaab018] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 02/09/2021] [Indexed: 01/10/2023] Open
Abstract
About 40% of women with infertility and 70% of women with pelvic pain suffer from endometriosis. The pregnancy rate in women undergoing IVF with low endometrial integrin αvβ3 (LEI) expression is significantly lower compared to the women with high endometrial integrin αvβ3 (HEI). Mid-secretory eutopic endometrial biopsies were obtained from healthy controls (C; n=3), and women with HEI (n=4) and LEI (n=4) and endometriosis. Changes in gene expression were assessed using human gene arrays and DNA methylation data were derived using 385 K Two-Array Promoter Arrays. Transcriptional analysis revealed that LEI and C groups clustered separately with 396 differentially expressed genes (DEGs) (P<0.01: 275 up and 121 down) demonstrating that transcriptional and epigenetic changes are distinct in the LEI eutopic endometrium compared to the C and HEI group. In contrast, HEI vs C and HEI vs LEI comparisons only identified 83 and 45 DEGs, respectively. The methylation promoter array identified 1304 differentially methylated regions in the LEI vs C comparison. The overlap of gene and methylation array data identified 14 epigenetically dysregulated genes and quantitative RT-PCR analysis validated the transcriptomic findings. The analysis also revealed that aryl hydrocarbon receptor (AHR) was hypomethylated and significantly overexpressed in LEI samples compared to C. Further analysis validated that AHR transcript and protein expression are significantly (P<0.05) increased in LEI women compared to C. The increase in AHR, together with the altered methylation status of the 14 additional genes, may provide a diagnostic tool to identify the subset of women who have endometriosis-associated infertility.
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Affiliation(s)
- Niraj R Joshi
- Michigan State University, College of Human Medicine, Grand Rapids, MI, USA
| | | | | | - Jung Yoon Yoo
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea
| | - Karenne Fru
- Coastal Reproductive Endocrinology and Infertility, Wilmington, NC, USA
| | | | - Lingwen Yuan
- University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Shuk-Mei Ho
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jae-Wook Jeong
- Michigan State University, College of Human Medicine, Grand Rapids, MI, USA
| | - Steven L Young
- University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet 2021; 397:839-852. [PMID: 33640070 DOI: 10.1016/s0140-6736(21)00389-5] [Citation(s) in RCA: 582] [Impact Index Per Article: 145.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 08/09/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
Endometriosis is a common disease affecting 5-10% of women of reproductive age globally. However, despite its prevalence, diagnosis is typically delayed by years, misdiagnosis is common, and delivery of effective therapy is prolonged. Identification and prompt treatment of endometriosis are essential and facilitated by accurate clinical diagnosis. Endometriosis is classically defined as a chronic, gynaecological disease characterised by endometrial-like tissue present outside of the uterus and is thought to arise by retrograde menstruation. However, this description is outdated and no longer reflects the true scope and manifestations of the disease. The clinical presentation is varied, the presence of pelvic lesions is heterogeneous, and the manifestations of the disease outside of the female reproductive tract remain poorly understood. Endometriosis is now considered a systemic disease rather than a disease predominantly affecting the pelvis. Endometriosis affects metabolism in liver and adipose tissue, leads to systemic inflammation, and alters gene expression in the brain that causes pain sensitisation and mood disorders. The full effect of the disease is not fully recognised and goes far beyond the pelvis. Recognition of the full scope of the disease will facilitate clinical diagnosis and allow for more comprehensive treatment than currently available. Progestins and low-dose oral contraceptives are unsuccessful in a third of symptomatic women globally, probably as a result of progesterone resistance. Oral gonadotropin-releasing hormone (GnRH) antagonists constitute an effective and tolerable therapeutic alternative when first-line medications do not work. The development of GnRH antagonists has resulted in oral drugs that have fewer side-effects than other therapies and has allowed for rapid movement between treatments to optimise and personalise endometriosis care. In this Review, we discuss the latest understanding of endometriosis as a systemic disease with multiple manifestations outside the parameters of classic gynaecological disease.
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Affiliation(s)
- Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
| | - Alexander M Kotlyar
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Valerie A Flores
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
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21
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Mihara Y, Maekawa R, Sato S, Shimizu N, Doi-Tanaka Y, Takagi H, Shirafuta Y, Shinagawa M, Tamura I, Taketani T, Tamura H, Abe T, Asai Y, Sugino N. An Integrated Genomic Approach Identifies HOXC8 as an Upstream Regulator in Ovarian Endometrioma. J Clin Endocrinol Metab 2020; 105:5900720. [PMID: 32877504 DOI: 10.1210/clinem/dgaa618] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/28/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE To identify the upstream regulators (URs) involved in the onset and pathogenesis of ovarian endometrioma. METHODS Recently, a method called Significance-based Modules Integrating the Transcriptome and Epigenome (SMITE) that uses transcriptome data in combination with publicly available data for identifying URs of cellular processes has been developed. Here, we used SMITE with transcriptome data from ovarian endometrioma stromal cells (ovESCs) and eutopic endometrium stromal cells (euESCs) in combination with publicly available gene regulatory network data. To confirm the URs identified by SMITE, we developed a Boolean network simulation to see if correcting aberrant expressions of the identified genes could restore the entire gene expression profile of ovESCs to a profile similar to that of euESCs. We then established euESCs overexpressing the identified gene and characterized them by cell function assays and transcriptome analysis. RESULTS SMITE identified 12 potential URs in ovarian endometrioma that were confirmed by the Boolean simulation. One of the URs, HOXC8, was confirmed to be overexpressed in ovESCs. HOXC8 overexpression significantly enhanced cell proliferation, migration, adhesion, and fibrotic activities, and altered expression statuses of the genes involved in transforming growth factor (TGF)-β signaling. HOXC8 overexpression also increased the expression levels of phosphorylated SMAD2/SMAD3. The increased adhesion and fibrosis activities by HOXC8 were significantly inhibited by E-616452, a selective inhibitor of TGF-β receptor type I kinases. MAIN CONCLUSIONS Integrated genomic approaches identified HOXC8 as an UR in ovarian endometrioma. The pathological features of ovarian endometrioma including cell proliferation, adhesion, and fibrosis were induced by HOXC8 and its subsequent activation of TGF-β signaling.
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Affiliation(s)
- Yumiko Mihara
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Ryo Maekawa
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shun Sato
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Natsuko Shimizu
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yumiko Doi-Tanaka
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Haruka Takagi
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yuichiro Shirafuta
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masahiro Shinagawa
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Isao Tamura
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Toshiaki Taketani
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hiroshi Tamura
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Takeshi Abe
- Department of Systems Bioinformatics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yoshiyuki Asai
- Department of Systems Bioinformatics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Norihiro Sugino
- Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube, Japan
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22
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Guo SW. Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology. Hum Reprod Update 2020; 26:423-449. [PMID: 32154564 DOI: 10.1093/humupd/dmz047] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 10/22/2019] [Accepted: 11/19/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Endometriosis is a benign gynaecological disease. Thus, it came as a complete surprise when it was reported recently that the majority of deep endometriosis lesions harbour somatic mutations and a sizeable portion of them contain known cancer-associated mutations (CAMs). Four more studies have since been published, all demonstrating the existence of CAMs in different subtypes of endometriosis. While the field is still evolving, the confirmation of CAMs has raised many questions that were previously overlooked. OBJECTIVE AND RATIONALE A comprehensive overview of CAMs in endometriosis has been produced. In addition, with the recently emerged understanding of the natural history of endometriotic lesions as well as CAMs in normal and apparently healthy tissues, this review attempts to address the following questions: Why has there been such a wild discrepancy in reported mutation frequencies? Why does ectopic endometrium have a higher mutation rate than that of eutopic endometrium? Would the presence of CAMs in endometriotic lesions increase the risk of cancer to the bearers? Why do endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart? What clinical implications, if any, do the CAMs have for the bearers? Do these CAMs tell us anything about the pathogenesis and/or pathophysiology of endometriosis? SEARCH METHODS The PubMed database was searched, from its inception to September 2019, for all papers in English using the term 'endometriosis and CAM', 'endometriosis and cancer-driver mutation', 'somatic mutations', 'fibrosis', 'fibrosis and epigenetic', 'CAMs and tumorigenesis', 'somatic mutation and normal tissues', 'oestrogen receptor and fibrosis', 'oxidative stress and fibrosis', 'ARID1A mutation', and 'Kirsten rat sarcoma mutation and therapeutics'. All retrieved papers were read and, when relevant, incorporated into the review results. OUTCOMES Seven papers that identified CAMs in endometriosis using various sequencing methods were retrieved, and their results were somewhat different. Yet, it is apparent that those using microdissection techniques and more accurate sequencing methods found more CAMs, echoing recent discoveries that apparently healthy tissues also harbour CAMs as a result of the replicative aging process. Hence endometriotic lesions, irrespective of subtype, if left intact, would generate CAMs as part of replicative aging, oxidative stress and perhaps other factors yet to be identified and, in some rare cases, develop cancer. The published data still are unable to paint a clear picture on pathogenesis of endometriosis. However, since endometriotic epithelial cells have a higher turnover than their stromal counterpart due to cyclic bleeding, and since the endometriotic stromal component can be formed by refresh influx of mesenchymal cells through epithelial-mesenchymal transition, endothelial-mesenchymal transition, mesothelial-mesenchymal transition and other processes as well as recruitment of bone-marrow-derived stem cells and outflow due to smooth muscle metaplasia, endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart. The epithelial and stromal cellular components develop in a dependent and co-evolving manner. Genes involved in CAMs are likely to be active players in lesional fibrogenesis, and hyperestrogenism and oxidative stress are likely drivers of both CAMs and fibrogenesis. Finally, endometriotic lesions harbouring CAMs would conceivably be more refractory to medical treatment, due, in no small part, to their high fibrotic content and reduced vascularity and cellularity. WIDER IMPLICATIONS The accumulating data on CAMs in endometriosis have shed new light on the pathogenesis and pathophysiology of endometriosis. They also suggest new challenges in management. The distinct yet co-evolving developmental trajectories of endometriotic stroma and epithelium underscore the importance of the lesional microenvironment and ever-changing cellular identity. Mutational profiling of normal endometrium from women of different ages and reproductive history is needed in order to gain a deeper understanding of the pathogenesis. Moreover, one area that has conspicuously received scant attention is the epigenetic landscape of ectopic, eutopic and normal endometrium.
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Affiliation(s)
- Sun-Wei Guo
- Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai 200011, China
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23
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Zhao J, Wang L, Li Y, Zhao W, Kang S. Hypomethylation of the GSTM1 promoter is associated with ovarian endometriosis. Hum Reprod 2020; 34:804-812. [PMID: 30989213 DOI: 10.1093/humrep/dez039] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/16/2019] [Accepted: 02/27/2019] [Indexed: 01/10/2023] Open
Abstract
STUDY QUESTION Is the methylation status of the glutathione S-transferase M1 (GSTM1) promoter region altered in patients with ovarian endometriosis, and does this affect the expression of GSTM1 in their endometrial tissues? SUMMARY ANSWER The promoter region of GSTM1 was significantly hypomethylated in the ectopic and eutopic endometrium of patients with ovarian endometriosis and this was associated with higher expression of GSTM1 mRNA. WHAT IS KNOWN ALREADY GSTM1, a member of the glutathione S-transferase family, is primarily known as a detoxification enzyme, but it has also been shown to negatively regulate apoptosis-related signalling cascades through protein-protein interactions with apoptosis signal-regulating kinase-1. STUDY DESIGN, SIZE, DURATION This is a case-control study between September 2013 and December 2016, involving 65 patients with ovarian endometriosis and 53 women without endometriosis. We analysed the methylation status and expression levels of GSTM1 in the ectopic and eutopic endometrium of patients with ovarian endometriosis and the endometrium of women without endometriosis. In addition, we collected endometrial samples from 12 women without endometriosis for endometrial epithelial cell cultures. PARTICIPANTS/MATERIALS, SETTING, METHODS Methylation levels of the GSTM1 promoter region in the ectopic and eutopic endometrial tissues of patients with ovarian endometriosis and the endometrial tissues of women without endometriosis were analysed by pyrosequencing. The expression of GSTM1 mRNA and protein in endometrial tissues was investigated by RT-qPCR and immunohistochemistry, respectively. Primary cell culture, gene transfection, Cell Counting Kit-8 assay and flow cytometry were used to analyse the effect of GSTM1 on viability and apoptosis in endometrial epithelial cells. MAIN RESULTS AND THE ROLE OF CHANCE Compared with that in the endometrium of women without endometriosis, the GSTM1 promoter region was significantly hypomethylated in the ectopic and eutopic endometrium of patients with ovarian endometriosis. Additionally, GSTM1 mRNA and protein levels were significantly higher in the ectopic and eutopic endometrium than in the control endometrium. Moreover, the methylation levels of the GSTM1 promoter region were significantly negatively correlated with the mRNA expression of GSTM1. Furthermore, in vitro results suggested that the over-expression of GSTM1 could significantly increase viability and inhibit apoptosis in endometrial epithelial cells following hormone treatment and withdrawal. LIMITATIONS, REASONS FOR CAUTION Due to restrictions in the isolation and culture of pure populations of endometrial epithelial cells, as well as limitations in the number of passages possible in primary cells, we could not explore the underlying molecular mechanism by which GSTM1 modulates apoptosis in endometrial cells. WIDER IMPLICATIONS OF THE FINDINGS This study provides new evidence to support the notion that endometriosis may be an epigenetic disease. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants from the Natural Science Foundation of Hebei Province (Grant number: H2018206200) and the Department of Education of Hebei Province (Grant number: CXZZBS2017114). The authors have no conflicts of interest to declare.
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Affiliation(s)
- Jian Zhao
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Lixian Wang
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Yan Li
- Department of Molecular Biology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Wei Zhao
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, PR China
| | - Shan Kang
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, PR China
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24
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Prašnikar E, Knez J, Kovačič B, Kunej T. Molecular signature of eutopic endometrium in endometriosis based on the multi-omics integrative synthesis. J Assist Reprod Genet 2020; 37:1593-1611. [PMID: 32474803 PMCID: PMC7376782 DOI: 10.1007/s10815-020-01833-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/14/2020] [Indexed: 12/31/2022] Open
Abstract
PURPOSE To synthesise data from genome-wide studies reporting molecular signature of eutopic endometrium through the phases of the menstrual cycle in endometriosis. METHODS Extraction of data from publications reporting genetic signatures characterising endometrium associated with endometriosis. The nomenclature of extracted differentially expressed transcripts and proteins was adopted according to the HUGO Gene Nomenclature Committee (HGNC). Loci were further sorted according to the different phases of the menstrual cycle, i.e. menstrual (M), proliferative (P), secretory (S), early-secretory (ES), mid-secretory (MS), late-secretory (LS), and not specified (N/S) if the endometrial dating was not available. Enrichment analysis was performed using the DAVID bioinformatics tool. RESULTS Altered molecular changes were reported by 21 studies, including 13 performed at the transcriptomic, 6 at proteomic, and 2 at epigenomic level. Extracted data resulted in a catalogue of total 670 genetic causes with available 591 official gene symbols, i.e. M = 3, P = 188, S = 81, ES = 82, MS = 173, LS = 36, and N/S = 28. Enriched pathways included oestrogen signalling pathway, extracellular matrix organization, and endothelial cell chemotaxis. Our study revealed that knowledge of endometrium biology in endometriosis is fragmented due to heterogeneity of published data. However, 15 genes reported as dysregulated by at least two studies within the same phase and 33 significantly enriched GO-BP terms/KEGG pathways associated with different phases of the menstrual cycle were identified. CONCLUSIONS A multi-omics insight into molecular patterns underlying endometriosis could contribute towards identification of endometrial pathological mechanisms that impact fertility capacities of women with endometriosis.
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Affiliation(s)
- Erika Prašnikar
- Department of Reproductive Medicine and Gynecological Endocrinology, University Medical Centre Maribor, 2000, Maribor, Slovenia
| | - Jure Knez
- Department of Gynecological and Breast Oncology, University Medical Centre Maribor, 2000, Maribor, Slovenia
| | - Borut Kovačič
- Department of Reproductive Medicine and Gynecological Endocrinology, University Medical Centre Maribor, 2000, Maribor, Slovenia.
| | - Tanja Kunej
- Biotechnical Faculty, Department of Animal Science, University of Ljubljana, 1000, Ljubljana, Slovenia.
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25
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Zubrzycka A, Zubrzycki M, Perdas E, Zubrzycka M. Genetic, Epigenetic, and Steroidogenic Modulation Mechanisms in Endometriosis. J Clin Med 2020; 9:E1309. [PMID: 32370117 PMCID: PMC7291215 DOI: 10.3390/jcm9051309] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/24/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Endometriosis is a chronic gynecological disease, affecting up to 10% of reproductive-age women. The exact cause of the disease is unknown; however, it is a heritable condition affected by multiple genetic, epigenetic, and environmental factors. Previous studies reported variations in the epigenetic patterns of numerous genes known to be involved in the aberrant modulation of cell cycle steroidogenesis, abnormal hormonal, immune and inflammatory status in endometriosis, apoptosis, adhesion, angiogenesis, proliferation, immune and inflammatory processes, response to hypoxia, steroidogenic pathway and hormone signaling are involved in the pathogenesis of endometriosis. Accumulating evidence suggest that various epigenetic aberrations may contribute to the pathogenesis of endometriosis. Among them, DNA methyltransferases, histone deacetylators, and non-coding microRNAs demonstrate differential expression within endometriotic lesions and in the endometrium of patients with endometriosis. It has been indicated that the identification of epigenetic differences within the DNA or histone proteins may contribute to the discovery of a useful prognostic biomarker, which could aid in the future earlier detection, timely diagnosis, and initiation of a new approach to the treatment of endometriosis, as well as inform us about the effectiveness of treatment and the stage of the disease. As the etiology of endometriosis is highly complex and still far from being fully elucidated, the presented review focuses on different approaches to identify the genetic and epigenetic links of endometriosis and its pathogenesis.
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Affiliation(s)
- Anna Zubrzycka
- Department of Biomedicine and Genetics, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland; Poland;
- Department of Operative and Conservative Gynecology, K. Jonscher Memorial Hospital, Milionowa 14, 93-113 Lodz, Poland
| | - Marek Zubrzycki
- Department of Cardiac Surgery and Transplantology, The Cardinal Stefan Wyszynski Institute of Cardiology, Alpejska 42, 04-628 Warsaw, Poland;
| | - Ewelina Perdas
- Department of Cardiovascular Physiology, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland;
| | - Maria Zubrzycka
- Department of Cardiovascular Physiology, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland;
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26
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Giampaolino P, Della Corte L, Foreste V, Barra F, Ferrero S, Bifulco G. Dioxin and endometriosis: a new possible relation based on epigenetic theory. Gynecol Endocrinol 2020; 36:279-284. [PMID: 31805795 DOI: 10.1080/09513590.2019.1698024] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Endometriosis is a chronic disease characterized by the growth of endometrial-like glands and stroma outside the uterine cavity. Nowadays, the exact etiology of endometriosis is unclear and the interaction between a variety of environmental physical and chemical compounds may potentially promote the disease in women with an individual susceptibility. The first demonstration of a relation between an environmental factor and endometriosis was obtained with the chronic dietary exposure of a primate colony to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Besides the well-known dioxin's pathway of action, several papers are focusing on the role of epigenetic mechanisms, a way through which the genome responds to the environment and can lead to permanent changes in gene expression until affecting the phenotypes or cause disease. In this review, we focus on the possible role of dioxin epigenetics modification in endometriosis.
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Affiliation(s)
| | - Luigi Della Corte
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Virginia Foreste
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Fabio Barra
- Academic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Simone Ferrero
- Academic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Giuseppe Bifulco
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
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27
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Goulielmos GN, Matalliotakis M, Matalliotaki C, Eliopoulos E, Matalliotakis I, Zervou MI. Endometriosis research in the -omics era. Gene 2020; 741:144545. [PMID: 32165309 DOI: 10.1016/j.gene.2020.144545] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/28/2020] [Accepted: 03/08/2020] [Indexed: 12/18/2022]
Abstract
Endometriosis is a pathological condition extensively studied, but its pathogenesis is not completely understood, since its pathophysiology stems from a broad spectrum of environmental influences and genetic factors. Moreover, the nature of this condition is heterogeneous and includes different anatomical entities. Scientists actively pursue discovery of novel biomarkers in the hope of better identifying susceptible individuals in early stages of the disease. High-throughput technologies have substantially revolutionized medical research and, as a first step, the advent of genotyping arrays led to large-scale genome-wide association studies (GWAS) and enabled the assessment of global transcript levels, thus giving rise to integrative genetics. In this framework, comprehensive studies have been conducted at multiple biological levels by using the "omics" platforms, thus allowing to re-examine endometriosis at a greater degree of molecular resolution. -Omics technologies can detect and analyze hundreds of markers in the same experiment and their increasing use in the field of gynecology comes from an urgent need to find new diagnostic and therapeutic tools that improve the diagnosis of endometriosis and the efficacy of assisted reproductive techniques. Proteomics and metabolomics have been introduced recently into the every day methodology of researchers collaborating with gynecologists and, importantly, multi-omics approach is advantageous to gain insight of the total information that underlies endometriosis, compared to studies of any single -omics type. In this review, we expect to present multiple studies based on the high-throughput-omics technologies and to shed light in all considerable advantages that they may confer to a proper management of endometriosis.
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Affiliation(s)
- George N Goulielmos
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine School of Medicine, University of Crete, Heraklion, Greece
| | - Michail Matalliotakis
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine School of Medicine, University of Crete, Heraklion, Greece; Third Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece; Department of Obstetrics and Gynecology, Venizeleio and Pananio General Hospital of Heraklion, Heraklion, Greece
| | - Charoula Matalliotaki
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine School of Medicine, University of Crete, Heraklion, Greece; Third Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece; Department of Obstetrics and Gynecology, Venizeleio and Pananio General Hospital of Heraklion, Heraklion, Greece
| | - Elias Eliopoulos
- Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Ioannis Matalliotakis
- Department of Obstetrics and Gynecology, Venizeleio and Pananio General Hospital of Heraklion, Heraklion, Greece
| | - Maria I Zervou
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine School of Medicine, University of Crete, Heraklion, Greece.
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Gerkowicz SA, Curtis SW, Knight AK, Cobb DO, Spencer JB, Conneely KN, Terrell ML, Marcus M, Smith AK. Endometriosis, endocrine disrupters, and epigenetics: an investigation into the complex interplay in women with polybrominated biphenyl exposure and endometriosis. J Assist Reprod Genet 2020; 37:427-436. [PMID: 32026200 PMCID: PMC7056781 DOI: 10.1007/s10815-020-01695-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 01/10/2020] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Endocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB). METHODS Cross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the β value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings. RESULTS In total, 39,877 CpGs nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity, although none remained significant after correction for multiple comparisons (FDR < 0.05). Pathway analysis of these CpGs showed enrichment in 68 biologic pathways involved in various endocrine, immunologic, oncologic, and cell regulation processes as well as embryologic reproductive tract development and function (FoxO, Wnt, and Hedgehog signaling). We identified 42,261 CpG sites in the literature reported to be associated with endometriosis; 2012 of these CpG sites were also significant in our cohort. CONCLUSION We found 39,877 CpG sites that nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity; however, none remained significant after correction for multiple comparisons (FDR < 0.05).
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Affiliation(s)
- Sabrina A Gerkowicz
- Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology and Infertility, Emory University, Atlanta, GA, USA
| | - Sarah W Curtis
- Genetics and Molecular Biology Program, Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA
| | - Anna K Knight
- Department of Gynecology and Obstetrics, Emory University, 101 Woodruff Circle NE, Suite 4217, Atlanta, GA, 30322, USA
| | - Dawayland O Cobb
- Department of Gynecology and Obstetrics, Emory University, 101 Woodruff Circle NE, Suite 4217, Atlanta, GA, 30322, USA
| | - Jessica B Spencer
- Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology and Infertility, Emory University, Atlanta, GA, USA
| | - Karen N Conneely
- Genetics and Molecular Biology Program, Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA
| | - Metrecia L Terrell
- Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Michele Marcus
- Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Alica K Smith
- Department of Gynecology and Obstetrics, Emory University, 101 Woodruff Circle NE, Suite 4217, Atlanta, GA, 30322, USA.
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle NE, Suite 4217, Atlanta, GA, 30322, USA.
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29
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Mahajan V, Farquhar C, Ponnampalam AP. Could DNA hydroxymethylation be crucial in influencing steroid hormone signaling in endometrial biology and endometriosis? Mol Reprod Dev 2019; 87:7-16. [PMID: 31749216 DOI: 10.1002/mrd.23299] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
Endometriosis affects 10% of reproductive-aged women. It is characterized by the growth of the endometrium, outside the uterus and is associated with infertility and chronic abdominal pain. Lack of noninvasive diagnostic tools and early screening tests results in delayed treatment and subsequently increased disease severity. Endometriosis is a disease associated with a deregulated hormonal response, therefore, understanding the molecular mechanisms that govern this hormonal interplay is of paramount importance. DNA methylation is an epigenetic mark that regulates gene expression and is often associated with genes that code for steroid receptors and enzymes associated with estrogen synthesis and metabolism in endometriosis. DNA hydroxymethylation, which is structurally similar to methylation but functionally different, is a biologically critical mechanism that is also known to regulate gene expression. Ten Eleven Translocation (TET) proteins mediate hydroxymethylation. However, the role of DNA hydroxymethylation or TETs in the endometrium remains relatively unexplored. Currently, the "gold standard" technique used to study methylation patterns is bisulfite genomic sequencing. This technique also detects hydroxymethylation but fails to distinguish between the two, thereby limiting our understanding of these two processes. The presence of TETs in the male and female reproductive tract and its contribution to endometrial cancer makes it an important factor to study in endometriosis. This review summarizes the role of DNA methylation in aberrant steroid hormone signaling and hypothesizes that hydroxymethylation could be a factor influencing hormonal instability seen in endometriosis.
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Affiliation(s)
- Vishakha Mahajan
- The Liggins Institute, The University of Auckland, Auckland, New Zealand
| | - Cynthia Farquhar
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Anna P Ponnampalam
- The Liggins Institute, The University of Auckland, Auckland, New Zealand.,Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.,Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
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30
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Saare M, Krigul KL, Laisk-Podar T, Ponandai-Srinivasan S, Rahmioglu N, Lalit Kumar PG, Zondervan K, Salumets A, Peters M. DNA methylation alterations-potential cause of endometriosis pathogenesis or a reflection of tissue heterogeneity? Biol Reprod 2019; 99:273-282. [PMID: 29796617 DOI: 10.1093/biolre/ioy067] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 03/20/2018] [Indexed: 01/10/2023] Open
Abstract
Alterations in the DNA methylation pattern of endometriotic lesions and endometrium of endometriosis patients have been proposed as one potential factor accompanying the endometriosis development. Although many differentially methylated genes have been associated with the pathogenesis of this disease, the overlap between the results of different studies has remained small. Among other potential confounders, the impact of tissue heterogeneity on the outcome of DNA methylation studies should be considered, as tissues are mixtures of different cell types with their own specific DNA methylation signatures. This review focuses on the results of DNA methylation studies in endometriosis from the cellular heterogeneity perspective. We consider both the studies using highly heterogeneous whole-lesion biopsies and endometrial tissue, as well as pure cell fractions isolated from lesions and endometrium to understand the potential impact of the cellular composition to the results of endometriosis DNA methylation studies. Also, future perspectives on how to diminish the impact of tissue heterogeneity in similar studies are provided.
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Affiliation(s)
- Merli Saare
- Competence Centre on Health Technologies, Tartu, Estonia.,Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia
| | - Kertu Liis Krigul
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Triin Laisk-Podar
- Competence Centre on Health Technologies, Tartu, Estonia.,Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia
| | | | - Nilufer Rahmioglu
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.,Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Parameswaran Grace Lalit Kumar
- Division of Obstetrics and Gynecology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Krina Zondervan
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.,Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Andres Salumets
- Competence Centre on Health Technologies, Tartu, Estonia.,Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia.,Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Insitute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Maire Peters
- Competence Centre on Health Technologies, Tartu, Estonia.,Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia
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31
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Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P, Milad M, Wei J. Endometriosis. Endocr Rev 2019; 40:1048-1079. [PMID: 30994890 PMCID: PMC6693056 DOI: 10.1210/er.2018-00242] [Citation(s) in RCA: 485] [Impact Index Per Article: 80.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 04/08/2019] [Indexed: 02/08/2023]
Abstract
Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It is caused when shed endometrial tissue travels retrograde into the lower abdominal cavity. Endometriosis is the most common cause of chronic pelvic pain in women and is associated with infertility. The underlying pathologic mechanisms in the intracavitary endometrium and extrauterine endometriotic tissue involve defectively programmed endometrial mesenchymal progenitor/stem cells. Although endometriotic stromal cells, which compose the bulk of endometriotic lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities that alter expression of key transcription factors. For example, GATA-binding factor-6 overexpression transforms an endometrial stromal cell to an endometriotic phenotype, and steroidogenic factor-1 overexpression causes excessive production of estrogen, which drives inflammation via pathologically high levels of estrogen receptor-β. Progesterone receptor deficiency causes progesterone resistance. Populations of endometrial and endometriotic epithelial cells also harbor multiple cancer driver mutations, such as KRAS, which may be associated with the establishment of pelvic endometriosis or ovarian cancer. It is not known how interactions between epigenomically defective stromal cells and the mutated genes in epithelial cells contribute to the pathogenesis of endometriosis. Endometriosis-associated pelvic pain is managed by suppression of ovulatory menses and estrogen production, cyclooxygenase inhibitors, and surgical removal of pelvic lesions, and in vitro fertilization is frequently used to overcome infertility. Although novel targeted treatments are becoming available, as endometriosis pathophysiology is better understood, preventive approaches such as long-term ovulation suppression may play a critical role in the future.
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Affiliation(s)
- Serdar E Bulun
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Bahar D Yilmaz
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Christia Sison
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Kaoru Miyazaki
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Lia Bernardi
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Shimeng Liu
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Amanda Kohlmeier
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Ping Yin
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Magdy Milad
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - JianJun Wei
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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32
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Barjaste N, Shahhoseini M, Afsharian P, Sharifi-Zarchi A, Masoudi-Nejad A. Genome-wide DNA methylation profiling in ectopic and eutopic of endometrial tissues. J Assist Reprod Genet 2019; 36:1743-1752. [PMID: 31273584 DOI: 10.1007/s10815-019-01508-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/13/2019] [Indexed: 11/26/2022] Open
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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Affiliation(s)
- Nadia Barjaste
- Laboratory of Bioinformatics and Systems Biology, Department of Bioinformatics, University of Tehran, Kish International Campus, Kish, Iran
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Maryam Shahhoseini
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Parvaneh Afsharian
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Ali Sharifi-Zarchi
- Department of Computer Engineering, Sharif University of Technology, Tehran, Iran
| | - Ali Masoudi-Nejad
- Laboratory of Bioinformatics and Systems Biology, Department of Bioinformatics, University of Tehran, Kish International Campus, Kish, Iran.
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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Wang L, Zhao J, Li Y, Wang Z, Kang S. Genome-wide analysis of DNA methylation in endometriosis using Illumina Human Methylation 450 K BeadChips. Mol Reprod Dev 2019; 86:491-501. [PMID: 30740831 DOI: 10.1002/mrd.23127] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 01/17/2019] [Accepted: 01/24/2019] [Indexed: 12/13/2022]
Abstract
Endometriosis is a common chronic gynecologic disorder characterized by the presence and growth of endometrial-like tissue outside of the uterine cavity. Although the exact etiology remains unclear, epigenetic modifications, such as DNA methylation, are thought to contribute to the pathogenesis of endometriosis. Here, we used the Illumina Human Methylation 450 K BeadChip Array to analyze the genome-wide DNA methylation profiles of six endometriotic lesions and six eutopic endometria from patients with ovarian endometriosis and six endometria of women without endometriosis. Compared with the eutopic endometria of women with endometriosis, 12,159 differentially methylated CpG sites and 375 differentially methylated promoter regions were identified in endometriotic lesions. GO analyses showed that these putative differentially methylated genes were primarily associated with immune response, inflammatory response, response to steroid hormone stimulus, cell adhesion, negative regulation of apoptosis, and activation of the MAPK activity. In addition, the expression levels of DNMT1, DNMT3A, DNMT3B, and MBD2 in endometriotic lesions and eutopic endometria were significantly decreased compared with control endometria. Our findings suggest that aberrant DNA methylation status in endometriotic lesions may play a significant role in the pathogenesis and progression of endometriosis.
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Affiliation(s)
- Lixian Wang
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jian Zhao
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yan Li
- Department of Molecular Biology, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zihe Wang
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shan Kang
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
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34
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García-Gómez E, Vázquez-Martínez ER, Reyes-Mayoral C, Cruz-Orozco OP, Camacho-Arroyo I, Cerbón M. Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis. Front Endocrinol (Lausanne) 2019; 10:935. [PMID: 32063886 PMCID: PMC7000463 DOI: 10.3389/fendo.2019.00935] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
Endometriosis is a gynecological disorder characterized by the growth of endometrial tissue (glands and stroma) outside the uterus, mainly in the peritoneal cavity, ovaries, and intestines. This condition shows estrogen dependency and progesterone resistance, and it has been associated with chronic inflammation, severe pain, and infertility, which negatively affect the quality of life in reproductive women. The molecular mechanisms involved in the pathogenesis of endometriosis are not completely understood; however, inflammation plays a key role in the pathophysiology of the disease, mainly by altering the function of immune cells (macrophages, natural killer, and T cells) and increasing levels of pro-inflammatory mediators in the peritoneal cavity, endometrium, and blood. These immune alterations inhibit apoptotic pathways and promote adhesion and proliferation of endometriotic cells, as well as angiogenesis and neurogenesis in endometriotic lesions. It has been demonstrated that hormonal alterations in endometriosis are related to the inflammatory unbalance in this disease. Particularly, steroid hormones (mainly estradiol) promote the expression and release of pro-inflammatory factors. Excessive inflammation in endometriosis contributes to changes of hormonal regulation by modulating sex steroid receptors expression and increasing aromatase activity. In addition, dysregulation of the inflammasome pathway, mediated by an alteration of cellular responses to steroid hormones, participates in disease progression through preventing cell death, promoting adhesion, invasion, and cell proliferation. Furthermore, inflammation is involved in endometriosis-associated infertility, which alters endometrium receptivity by impairing biochemical responses and decidualization. The purpose of this review is to present current research about the role of inflammasome in the pathogenesis of endometriosis as well as the molecular role of sex hormones in the inflammatory responses in endometriosis.
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Affiliation(s)
- Elizabeth García-Gómez
- Unidad de Investigación en Reproducción Humana, Consejo Nacional de Ciencia y Tecnología (CONACyT)-Instituto Nacional de Perinatología, Mexico City, Mexico
- *Correspondence: Elizabeth García-Gómez
| | - Edgar Ricardo Vázquez-Martínez
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | | | - Ignacio Camacho-Arroyo
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Marco Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
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35
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Signorile PG, Severino A, Santoro M, Spyrou M, Viceconte R, Baldi A. Methylation analysis of HOXA10 regulatory elements in patients with endometriosis. BMC Res Notes 2018; 11:722. [PMID: 30309386 PMCID: PMC6182800 DOI: 10.1186/s13104-018-3836-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/09/2018] [Indexed: 11/30/2022] Open
Abstract
Objective The pathogenesis of endometriosis is still mysterious, being retrograde menstruation and coelomic metaplasia the most accepted hypotheses. Recently, it has been proposed that endometriosis is caused by fine-tuning alterations of the female genital system development during the foetal life and that in utero exposition to endocrine disruptors can be one of the factors causing the disease, possibly acting on the methylation status of the genome. In this study, we have evaluated the methylation status of HOXA10 gene regulation regions in a cohort of 22 endometriosis patients respect to a control group of 6 healthy women. Results The methylation study was carried out on three CpG islands, previously described hypermethylated in the endometrium of endometriosis patients and include 22 CpG sites, 21 CpG sites and 10 CpG sites, respectively identified through the online platform MethPrimer. The analysis did not find significant differences between patients with endometriosis and healthy control individuals. These results confirm previous studies on genome wide methylation analysis in endometriosis patients. Therefore, other epigenetically altered genes should be considered more related to the pathogenesis of endometriosis.
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Affiliation(s)
| | - Anna Severino
- Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
| | | | | | | | - Alfonso Baldi
- Fondazione Italiana Endometriosi, Rome, Italy. .,Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy.
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36
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Guo S. Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis. Reprod Med Biol 2018; 17:369-397. [PMID: 30377392 PMCID: PMC6194252 DOI: 10.1002/rmb2.12221] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/03/2018] [Accepted: 06/24/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND One recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation. METHODS Extensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review. RESULTS All six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings. CONCLUSIONS Given that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.
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Affiliation(s)
- Sun‐Wei Guo
- Shanghai Obstetrics and Gynecology HospitalFudan UniversityShanghaiChina
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related DiseasesShanghaiChina
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37
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Groothuis PG, Guo SW. Drug Development in Endometriosis and Adenomyosis: It Takes More Than Just Good Science. Reprod Sci 2018; 25:1318-1329. [DOI: 10.1177/1933719118785767] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Patrick G. Groothuis
- Preclinical Department, Synthon Biopharmaceuticals bv, Nijmegen, the Netherlands
| | - Sun-Wei Guo
- Shanghai OB/GYN Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
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38
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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; 26:88-96. [DOI: 10.1177/1933719118766255] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Yasaman Samadieh
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Raha Favaedi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Fariba Ramezanali
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Parvaneh Afsharian
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Reza Aflatoonian
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Maryam Shahhoseini
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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Hufnagel D, Goetz TG, Hu Z, Nyachieo A, D'Hooghe T, Fazleabas A, Duleba A, Krikun G, Taylor HS, Lockwood CJ. Icon immunoconjugate treatment results in regression of red lesions in a non-human primate (Papio anubis) model of endometriosis. Reprod Biol 2018; 18:109-114. [PMID: 29422377 DOI: 10.1016/j.repbio.2018.01.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/20/2018] [Accepted: 01/26/2018] [Indexed: 12/24/2022]
Abstract
Endometriosis is a common condition in reproductive-aged women characterized by ectopic endometrial lesions of varied appearance, including red, white, blue, black or powder burn coloration, which contribute to chronic pain and infertility. The immunoconjugate molecule (Icon) targets Tissue Factor, a transmembrane receptor for Factor VII/VIIa that is aberrantly expressed in the endothelium supporting ectopic endometrial tissue. Icon has been shown to cause regression of endometriosis in a murine model of disease but prior to this study had not been tested in non-human primates. This study evaluated Icon as a novel treatment for endometriosis in non-human primates (Papio anubis) using an adenoviral vector (AdIcon) delivery system. Female baboons (n = 15) underwent surgical induction of endometriosis. After laparoscopic confirmation of endometriosis lesions 6-weeks post-surgery, the treatment group (n = 7) received weekly intraperitoneal injections of viral particles carrying the sequence for Icon, resulting in expression of the protein, while the control group (n = 8) received no treatment. Icon preferentially reduced the number and volume of red vascularized lesions. Icon may present a novel treatment for endometriosis by degrading red vascularized lesions, likely by targeting tissue factor aberrantly expressed in the lesion vasculature.
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Affiliation(s)
- Demetra Hufnagel
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States
| | - Teddy G Goetz
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States
| | - Zhiwei Hu
- Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Atunga Nyachieo
- Department of Reproductive Health and Non-Communicable Diseases, Institute of Primate Research, Nairobi, Kenya
| | - Thomas D'Hooghe
- Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Campus Gasthuisberg, Leuven, Belgium
| | - Asgerally Fazleabas
- Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, MI, United States
| | - Antoni Duleba
- Department of Reproductive Medicine, University of California San Diego, San Diego, CA, United States
| | - Graciela Krikun
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States.
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States
| | - Charles J Lockwood
- Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
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Colón-Caraballo M, Flores-Caldera I. Translational Aspects of the Endometriosis Epigenome. EPIGENETICS IN HUMAN DISEASE 2018:717-749. [DOI: 10.1016/b978-0-12-812215-0.00023-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Rahmioglu N, Drong AW, Lockstone H, Tapmeier T, Hellner K, Saare M, Laisk-Podar T, Dew C, Tough E, Nicholson G, Peters M, Morris AP, Lindgren CM, Becker CM, Zondervan KT. Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues. Epigenetics 2017; 12:897-908. [PMID: 29099281 PMCID: PMC5750814 DOI: 10.1080/15592294.2017.1367475] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Genome-wide association studies in the fields of reproductive medicine and endocrinology are yielding robust genetic variants associated with disease. Integrated genomic, transcriptomic, and epigenomic molecular profiling studies are common methodologies used to understand the biologic pathways perturbed by these variants. However, molecular profiling resources do not include the tissue most relevant to many female reproductive traits, the endometrium, while the parameters influencing variability of results from its molecular profiling are unclear. We investigated the sources of DNA methylation and RNA expression profile variability in endometrium (n = 135), endometriotic disease tissue (endometriosis), and subcutaneous abdominal fat samples from 24 women, quantifying between-individual, within-tissue (cellular heterogeneity), and technical variation. DNA samples (n = 96) were analyzed using Illumina HumanMethlylation450 BeadChip arrays; RNA samples (n = 39) were analyzed using H12-expression arrays. Variance-component analyses showed that, for the top 10–50% variable DNA methylation/RNA expression sites, between-individual variation far exceeded within-tissue and technical variation. Menstrual-phase accounted for most variability in methylation/expression patterns in endometrium (Pm = 7.8 × 10−3, Pe = 8.4 × 10−5) but not in fat and endometriotic tissue; age was significantly associated with DNA methylation profile of endometrium (Pm = 9 × 10−5) and endometriotic disease tissue (Pm = 2.4 × 10−5); and smoking was significantly associated with DNA methylation in adipose tissue (Pm = 1.8 × 10−3). Hierarchical cluster analysis showed significantly different methylation signatures between endometrium and endometriotic tissue enriched for WNT signaling, angiogenesis, cadherin signaling, and gonadotropin-releasing-hormone-receptor pathways. Differential DNA methylation/expression analyses suggested detection of a limited number of sites with large fold changes (FC > 4), but power calculations accounting for different sources of variability showed that for robust detection >500 tissue samples are required. These results enable appropriate study design for large-scale expression and methylation tissue-based profiling relevant to many reproductive and endocrine traits.
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Affiliation(s)
- Nilufer Rahmioglu
- a Wellcome Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford , OX3 7BN , UK
| | - Alexander W Drong
- a Wellcome Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford , OX3 7BN , UK
| | - Helen Lockstone
- a Wellcome Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford , OX3 7BN , UK
| | - Thomas Tapmeier
- b Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology , John Radcliffe Hospital, University of Oxford , Oxford , OX3 7BN , UK
| | - Karin Hellner
- b Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology , John Radcliffe Hospital, University of Oxford , Oxford , OX3 7BN , UK
| | - Merli Saare
- c Competence Centre on Health Technologies, Tartu, Estonia and Women's Clinic, Institute of Clinical Medicine, University of Tartu , Tartu , Estonia
| | - Triin Laisk-Podar
- c Competence Centre on Health Technologies, Tartu, Estonia and Women's Clinic, Institute of Clinical Medicine, University of Tartu , Tartu , Estonia
| | - Christine Dew
- b Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology , John Radcliffe Hospital, University of Oxford , Oxford , OX3 7BN , UK
| | - Emily Tough
- b Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology , John Radcliffe Hospital, University of Oxford , Oxford , OX3 7BN , UK
| | - George Nicholson
- a Wellcome Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford , OX3 7BN , UK
| | - Maire Peters
- c Competence Centre on Health Technologies, Tartu, Estonia and Women's Clinic, Institute of Clinical Medicine, University of Tartu , Tartu , Estonia
| | - Andrew P Morris
- a Wellcome Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford , OX3 7BN , UK.,d Department of Biostatistics , University of Liverpool , Liverpool , OX3 7BN , UK
| | - Cecilia M Lindgren
- a Wellcome Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford , OX3 7BN , UK
| | - Christian M Becker
- b Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology , John Radcliffe Hospital, University of Oxford , Oxford , OX3 7BN , UK
| | - Krina T Zondervan
- a Wellcome Centre for Human Genetics, University of Oxford , Roosevelt Drive, Oxford , OX3 7BN , UK.,b Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology , John Radcliffe Hospital, University of Oxford , Oxford , OX3 7BN , UK
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Logan PC, Yango P, Tran ND. Endometrial Stromal and Epithelial Cells Exhibit Unique Aberrant Molecular Defects in Patients With Endometriosis. Reprod Sci 2017; 25:140-159. [PMID: 28490276 DOI: 10.1177/1933719117704905] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
CONTEXT Endometriosis is a chronic inflammatory disease that causes pain and infertility in women of reproductive age. OBJECTIVE To investigate the pathologic pathways in endometrial stromal and epithelial cells that contribute to the manifestation of endometriosis. DESIGN In vitro cellular and molecular analyses of isolated eutopic endometrial stromal and epithelial cells. METHODS Eutopic stromal and epithelial cells from endometriotic and normal patients were isolated by fluorescence-activated cell sorting for paired sibling RNA sequencing and microRNA microarray. Aberrant pathways were identified using ingenuity pathway analysis networks and confirmed with in vitro modulation of the affected pathways in stromal and epithelial cell cultures. RESULTS Both stromal versus epithelial cell types and paired endometriotic versus normal samples exhibited distinct hierarchical clustering. Compared to normal samples, there were 151 and 215 differentially expressed genes in the endometriotic stromal and epithelial populations, respectively, and concomitantly 9 and 16 differentially expressed microRNAs. Overall, endometriotic stromal and epithelial cells revealed distinct defects. In endometriotic stromal cells, key decidualization genes Zinc finger E-box Binding protein 1 (ZEB1), Heart And Neural crest Derivatives expressed 2 (HAND2), WNT4, and Interleukin 15 (IL-15) were found to be downregulated and Periostin (POSTN) and Matrix Metallopeptidase 7 (MMP7) were upregulated. Specifically, ZEB1 was downregulated in stromal cells by aberrant elevation in miR-200b. In contrast, ZEB1 was found to be upregulated in endometriotic epithelial cells through associated upregulation of transforming growth factor β1 (TGFβ1), inducer of the TGFβ1-Bone Morphogenetic Protein 2 (BMP2)-MMP2-Prostaglandin-endoperoxide Synthase 2 (COX2)-ZEB1 pathway, which activates epithelial-mesenchymal transition. CONCLUSION Manifestation of endometriosis involves dysregulation of unique molecular pathways within the diseased endometrial stromal and epithelial cells in the endometrium. Targeting the cell type-specific defects may offer a novel approach to treating endometriosis.
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Affiliation(s)
- Philip C Logan
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Pamela Yango
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Nam D Tran
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA
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Ito F, Yamada Y, Shigemitsu A, Akinishi M, Kaniwa H, Miyake R, Yamanaka S, Kobayashi H. Role of Oxidative Stress in Epigenetic Modification in Endometriosis. Reprod Sci 2017; 24:1493-1502. [PMID: 28443478 DOI: 10.1177/1933719117704909] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Aberrant DNA methylation and histone modification are associated with an increased risk of reproductive disorders such as endometriosis. However, a cause-effect relationship between epigenetic mechanisms and endometriosis development has not been fully determined. This review provides current information based on oxidative stress in epigenetic modification in endometriosis. This article reviews the English-language literature on epigenetics, DNA methylation, histone modification, and oxidative stress associated with endometriosis in an effort to identify epigenetic modification that causes a predisposition to endometriosis. Oxidative stress, secondary to the influx of hemoglobin, heme, and iron during retrograde menstruation, is involved in the expression of CpG demethylases, ten-eleven translocation, and jumonji (JMJ). Ten-eleven translocation and JMJ recognize a wide range of endogenous DNA methyltransferases (DNMTs). The increased expression levels of DNMTs may be involved in the subsequent downregulation of the decidualization-related genes. This review supports the hypothesis that there are at least 2 distinct phases of epigenetic modification in endometriosis: the initial wave of iron-induced oxidative stress would be followed by the second big wave of epigenetic modulation of endometriosis susceptibility genes. We summarize the recent advances in our understanding of the underlying epigenetic mechanisms focusing on oxidative stress in endometriosis.
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Affiliation(s)
- Fuminori Ito
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
| | - Yuki Yamada
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
| | - Aiko Shigemitsu
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
| | - Mika Akinishi
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
| | - Hiroko Kaniwa
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
| | - Ryuta Miyake
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
| | - Shoichiro Yamanaka
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
| | - Hiroshi Kobayashi
- 1 Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
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Biomarkers in endometriosis: challenges and opportunities. Fertil Steril 2017; 107:523-532. [PMID: 28189296 DOI: 10.1016/j.fertnstert.2017.01.009] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 12/27/2016] [Accepted: 01/06/2017] [Indexed: 02/07/2023]
Abstract
Endometriosis is a debilitating gynecologic disease affecting millions of women across the world, with symptoms including dysmenorrhea, chronic pelvic pain, and infertility. Theorized to stem from the phenomenon of retrograde menstruation, the diagnosis of endometriosis is typically delayed by 8-10 years owing to misinterpretation of symptoms as common menstrual cramps in adolescent girls and young women. With increased incidence of endometriosis in young girls correlated with earlier menarche, the development of diagnostic biomarkers is imperative for diagnosing and treating women afflicted with endometriosis as early as we can. In the past few years, multiple reviews highlighted the list of potential diagnostic candidates in peritoneal fluid, blood, urine, and endometrial biopsies from endometriosis patients in different stages of disease and menstrual cycle. In this review, we explore the opportunities and challenges facing the field of diagnostic biomarkers for endometriosis. We highlight the importance of eutopic endometrium as a source of potential diagnostic biomarkers by looking at the expression levels of noncoding RNA in tissue as well as in blood. Finally, we discuss some of the challenges that hinder our efforts in validating candidate diagnostic biomarkers for endometriosis.
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45
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Yotova I, Hsu E, Do C, Gaba A, Sczabolcs M, Dekan S, Kenner L, Wenzl R, Tycko B. Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis. PLoS One 2017; 12:e0170859. [PMID: 28125717 PMCID: PMC5268815 DOI: 10.1371/journal.pone.0170859] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 01/11/2017] [Indexed: 12/15/2022] Open
Abstract
Endometriosis is characterized by growth of endometrial-like tissue outside the uterine cavity. Since its pathogenesis may involve epigenetic changes, we used Illumina 450K Methylation Beadchips to profile CpG methylation in endometriosis stromal cells compared to stromal cells from normal endometrium. We validated and extended the Beadchip data using bisulfite sequencing (bis-seq), and analyzed differential methylation (DM) at the CpG-level and by an element-level classification for groups of CpGs in chromatin domains. Genes found to have DM included examples encoding transporters (SLC22A23), signaling components (BDNF, DAPK1, ROR1, and WNT5A) and transcription factors (GATA family, HAND2, HOXA cluster, NR5A1, OSR2, TBX3). Intriguingly, among the TF genes with DM we also found JAZF1, a proto-oncogene affected by chromosomal translocations in endometrial stromal tumors. Using RNA-Seq we identified a subset of the DM genes showing differential expression (DE), with the likelihood of DE increasing with the extent of the DM and its location in enhancer elements. Supporting functional relevance, treatment of stromal cells with the hypomethylating drug 5aza-dC led to activation of DAPK1 and SLC22A23 and repression of HAND2, JAZF1, OSR2, and ROR1 mRNA expression. We found that global 5hmC is decreased in endometriotic versus normal epithelial but not stroma cells, and for JAZF1 and BDNF examined by oxidative bis-seq, found that when 5hmC is detected, patterns of 5hmC paralleled those of 5mC. Together with prior studies, these results define a consistent epigenetic signature in endometriosis stromal cells and nominate specific transcriptional and signaling pathways as therapeutic targets.
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Affiliation(s)
- Iveta Yotova
- Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
- Department of Gynecology and Gynecological Oncology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
- * E-mail:
| | - Emily Hsu
- Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
| | - Catherine Do
- Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
| | - Aulona Gaba
- Department of Gynecology and Gynecological Oncology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Matthias Sczabolcs
- Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
| | - Sabine Dekan
- Department of Experimental Pathology, Clinical Institute of Pathology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Lukas Kenner
- Department of Experimental Pathology, Clinical Institute of Pathology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
- Pathology Laboratory Animal Pathology University of Veterinary Medicine Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | - Rene Wenzl
- Department of Gynecology and Gynecological Oncology, University Clinic of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Benjamin Tycko
- Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
- Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
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Lestari SW, Rizki MD. Epigenetic: A new approach to etiology of infertility. MEDICAL JOURNAL OF INDONESIA 2017. [DOI: 10.13181/mji.v25i4.1504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Infertility is a complex disease which could be caused by male and female factors. The etiology from both factors needs further study. There are some approaches to understanding the etiology of infertility, one of them is epigenetic. Epigenetic modifications consist of DNA methylation, histone modifications, and chromatin remodelling. Male and female germinal cells undergo epigenetic modifications dynamically during differentiation into matured sperm and oocyte cells. In a male, the alteration of DNA methylation in spermatogenesis will cause oligo/asthenozoospermia. In addition, the histone methylation, acetylation, or other histone modification may lead sperm lose its ability to fertilize oocyte. Similarly, in a female, the alteration of DNA methylation and histone modification affects oogenesis, created aneuploidy in fertilized oocytes and resulted in embryonic death in the uterus. Alteration of these epigenetic modification patterns will cause infertility, both in male and female.
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47
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Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model. PLoS One 2016; 11:e0165347. [PMID: 27776183 PMCID: PMC5077092 DOI: 10.1371/journal.pone.0165347] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 10/10/2016] [Indexed: 01/08/2023] Open
Abstract
Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERα and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERα and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis.
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48
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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. [PMID: 27535958 PMCID: PMC5178151 DOI: 10.1095/biolreprod.116.140434] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 08/10/2016] [Indexed: 12/17/2022] Open
Abstract
Endometriosis is an estrogen-dependent, progesterone-resistant disorder largely derived from retrograde transplantation of menstrual tissue/cells into the pelvis, eliciting an inflammatory response, pelvic pain, and infertility. Eutopic endometrium (within the uterus), giving rise to pelvic disease, displays cycle-dependent transcriptomic, proteomic, and signaling abnormalities, and although its DNA methylation profiles dynamically change across the cycle in healthy women, studies in endometriosis are limited. Herein, we investigated the DNA methylome and associated gene expression in three phases of the cycle in eutopic endometrium of women with severe endometriosis versus controls, matched for ethnicity, medications, smoking, and no recent contraceptive steroid use. Genome-wide DNA methylation and gene expression were coassessed in each sample. Cycle phase was determined by histology, serum hormone levels, and unsupervised principal component and hierarchical cluster analyses of microarray data. Altered endometrial DNA methylation in endometriosis was most prominent in the midsecretory phase (peak progesterone), with disruption of the normal pattern of cycle-dependent DNA methylation changes, including a bias toward methylation of CpG islands, suggesting wide-range abnormalities of the chromatin remodeling machinery in endometriosis. DNA methylation changes were associated with altered gene expression relevant to endometrial function/dysfunction, including cell proliferation, inflammation/immune response, angiogenesis, and steroid hormone response. The data provide insight into epigenetic reprogramming and steroid hormone actions in endometrium contributing to the pathogenesis and pathophysiology of endometriosis.
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Affiliation(s)
- Sahar Houshdaran
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California
| | - Camran R Nezhat
- Center for Special Minimally Invasive and Robotic Surgery, Palo Alto, California
| | - Kim Chi Vo
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California
| | - Zara Zelenko
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California
| | - Juan C Irwin
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California
| | - Linda C Giudice
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California
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Bruner-Tran KL, Gnecco J, Ding T, Glore DR, Pensabene V, Osteen KG. Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models. Reprod Toxicol 2016; 68:59-71. [PMID: 27423904 DOI: 10.1016/j.reprotox.2016.07.007] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/06/2016] [Accepted: 07/09/2016] [Indexed: 12/31/2022]
Abstract
Humans and other animals are exposed to a wide array of man-made toxicants, many of which act as endocrine disruptors that exhibit differential effects across the lifespan. In humans, while the impact of adult exposure is known for some compounds, the potential consequences of developmental exposure to endocrine disrupting chemicals (EDCs) is more difficult to ascertain. Animal studies have revealed that exposure to EDCs prior to puberty can lead to adult reproductive disease and dysfunction. Specifically, in adult female mice with an early life exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we demonstrated a transgenerational occurrence of several reproductive diseases that have been linked to endometriosis in women. Herein, we review the evidence for TCDD-associated development of adult reproductive disease as well as known epigenetic alterations associated with TCDD and/or endometriosis. We will also introduce new "Organ-on-Chip" models which, combined with our established murine model, are expected to further enhance our ability to examine alterations in gene-environment interactions that lead to heritable disease.
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Affiliation(s)
- Kaylon L Bruner-Tran
- Women's Reproductive Health Research Center, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
| | - Juan Gnecco
- Women's Reproductive Health Research Center, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Tianbing Ding
- Women's Reproductive Health Research Center, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Dana R Glore
- Women's Reproductive Health Research Center, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Virginia Pensabene
- Women's Reproductive Health Research Center, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Kevin G Osteen
- Women's Reproductive Health Research Center, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare System, Nashville TN 37212, USA
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50
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Sun Q, Ding D, Liu X, Guo SW. Tranylcypromine, a lysine-specific demethylase 1 (LSD1) inhibitor, suppresses lesion growth and improves generalized hyperalgesia in mouse with induced endometriosis. Reprod Biol Endocrinol 2016; 14:17. [PMID: 27062244 PMCID: PMC4826530 DOI: 10.1186/s12958-016-0154-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 04/05/2016] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Growing evidence indicates that endometriosis is an epigenetic disease. Encouragingly, histone deacetylases (HDACs) and DNA methyltransferases have been shown to be promising targets by numerous in vitro studies. However, only a few studies have shown promising effects of HDAC inhibition in preclinical studies in endometriosis. While lysine-specific demethylase 1 (LSD1) is recently found to be aberrantly expressed in endometriosis, and that the treatment of endometriotic stromal cells with tranylcypromine (TC), an LSD1 inhibitor, significantly reduced cellular proliferation, cell cycle progression, and invasiveness, the in vivo effect of TC treatment is currently lacking. This study sought to evaluate the effect of TC in a mouse model of endometriosis. METHODS Forty-seven female C57BL/6 mice were used in this experimentation. All mice, except those randomly selected to form Sham surgery (M) and specificity control (S) groups, received an endometriosis-inducing surgery. Group S was set up mainly to ensure that the reduced generalized hyperalgesia in mice treated with TC is not due to any possible analgesic effect of TC, but rather resulting from the treatment effect specific to endometriosis. Two weeks after the surgery, mice that received surgery were further divided randomly into 3 groups: 1) untreated group (U); 2) low-dose TC group (L); 3) high-dose TC group (H). Group S received the same treatment as in group H. Two weeks after treatment, all mice were sacrificed and their ectopic endometrial tissues were harvested and analyzed by immunohistochemistry analysis. Hotplate test was administrated to all mice before the induction, treatment and sacrifice. Lesion size, hotplate latency, immunoreactivity against markers of proliferation, angiogenesis, H3K4 methylation, and of epithelial-mesenchymal transition (EMT). RESULTS TC treatment significantly and substantially reduced the lesion size and improved generalized hyperalgesia in a dose-dependent fashion in mice with induced endometriosis. In addition, TC treatment resulted in reduced immunoreactivity to biomarkers of proliferation, angiogenesis, and H3K4 methylation, leading to arrested EMT and lesion growth. CONCLUSION In light of our previously reported reduced cellular proliferation, cell cycle progression and invasiveness resulting from the LSD1 inhibition in in vitro studies, our data strongly suggest that LSD1 is a promising therapeutic target for endometriosis. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Qunyan Sun
- Cixi Child and Maternal Hospital, 1288 Er'Zhaotan Road, Baishalu, Cixi, Zhejiang, China
| | - Ding Ding
- Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai, 200011, China
| | - Xishi Liu
- Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
| | - Sun-Wei Guo
- Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
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