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      Epigenetic regulation of the pathological process in endometriosis

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          Abstract

          Background

          Endometriosis is one of the most common gynecological diseases that greatly compromises the quality of life in affected individuals. A growing body of evidence shows that the remodeling of retrograde endometrial tissues to the ectopic endometriotic lesions involves multiple epigenetic alterations, such as DNA methylation, histone modification, and micro RNA expression.

          Methods

          This article retrospectively reviewed the studies that were related to the epigenetic regulatory factors that contribute to the development and maintenance of endometriosis. A literature search was performed in order to collect scientific articles that were written in English by using the key words of “endometriosis,” “epigenetics,” “ DNA methylation,” “histone modification,” and “micro RNA.”

          Results

          Epigenetic modifications, including DNA methylation, histone modification, and micro RNA expression, are involved in the pathogenesis of endometriosis. These epigenetic players are regulated or tuned by microenvironmental cues, such as locally produced estradiol, proinflammatory cytokines, and hypoxic stress, and reciprocally regulate the process or response to those stimuli.

          Conclusion

          Understanding the molecular mechanisms that underlie these epigenetic regulatory processes would shed light on the etiology and/or progression of endometriosis and facilitate the development of novel therapeutic strategies.

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          Most cited references41

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          Acetylation Limits 53BP1 Association with Damaged Chromatin to Promote Homologous Recombination

          The pathogenic sequelae of BRCA1 mutation in human and mouse cells are mitigated by concomitant deletion of 53BP1, which binds histone H4 dimethylated at Lys20 (H4K20me2) to promote nonhomologous end-joining, suggesting a balance between BRCA1 and 53BP1 regulates DNA double-strand break (DSB) repair mechanism choice. Here, we document that acetylation is a key determinant of this balance. TIP60 acetyltransferase deficiency reduced BRCA1 at DSB chromatin with commensurate increases in 53BP1, while HDAC inhibition yielded the opposite effect. TIP60 -dependent H4 acetylation diminished 53BP1 binding to H4K20me2 in part through disruption of a salt bridge between H4K16 and Glu1551 in the 53BP1 Tudor domain. Moreover, TIP60 deficiency impaired HR and conferred sensitivity to PARP inhibition in a 53BP1-dependent manner. These findings demonstrate that acetylation in cis to H4K20me2 regulates relative BRCA1 and 53BP1 DSB chromatin occupancy to direct DNA repair mechanism.
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            Histone H4 deacetylation facilitates 53BP1 DNA damage signaling and double-strand break repair.

            53BP1 and other DNA damage response (DDR) proteins form foci at double-strand breaks (DSBs) which promote their repair by nonhomologous end joining (NHEJ). Focal accumulation of 53BP1 depends on the specific interaction of its tandem Tudor domain with dimethylated lysine 20 in histone H4 (H4K20me2). How 53BP1 foci dynamics are regulated is unclear since H4K20me2 is highly abundant, established largely in the absence of DNA damage, and uncertainty exists about the roles of candidate H4K20 methyltransferases in 53BP1 foci formation. Here, we show that 53BP1 foci assemble primarily on H4K20me2 established prior to DNA damage by the SETD8 and SUV420 methyltransferases rather than de novo H4K20 methylation mediated by MMSET/WHSC1. Moreover, we define a novel role for H4K16 acetylation in regulating 53BP1 foci dynamics. Concurrent acetylation at H4K16 antagonizes 53BP1 binding to extant H4K20me2 until DSBs elicit transient, localized H4 deacetylation that facilitates 53BP1 foci formation and NHEJ, and is associated with global repression of gene transcription. Our findings demonstrate that rapid induction of H4 deacetylation by DSBs affects multiple aspects of the DDR, and also suggest that antagonism of 53BP1 binding to H4K20me2 by H4K16 hyperacetylation may contribute to the efficacy of histone deacetylase inhibitors for cancer therapy.
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              Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5' CpG island in endometriosis.

              Endometriosis is an estrogen-dependent disease. Steroidogenic factor-1 (SF-1), a transcriptional factor essential for activation of multiple steroidogenic genes for estrogen biosynthesis, is undetectable in normal endometrial stromal cells and aberrantly expressed in endometriotic stromal cells. The objective of the study was to unravel the mechanism for differential SF-1 expression in endometrial and endometriotic stromal cells. We identified a CpG island flanking the SF-1 promoter and exon I region and determined its methylation patterns in endometrial and endometriotic cells. The study was conducted at Northwestern University. Eutopic endometrium from disease-free subjects (n = 8) and the walls of cystic endometriosis lesions of the ovaries (n = 8) were investigated. Stromal cells were isolated from these two types of tissues. Measures are mentioned in Results. SF-1 mRNA and protein levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells (P < 0.001). Bisulfite sequencing showed strikingly increased methylation in endometrial cells, compared with endometriotic cells (P < 0.001). Demethylation by 5-aza-2'-deoxycytidine increased SF-1 mRNA levels by up to 55.48-fold in endometrial cell (P < 0.05). Luciferase assays showed that the -85/+239 region bearing the CpG island regulated its activity (P < 0.01). Natural or in vitro methylation of this region strikingly reduced SF-1 promoter activity in both cell types (P < 0.01). Chromatin immunoprecipitation assay showed that methyl-CpG-binding domain protein 2 binds to the SF-1 promoter in endometrial but not endometriotic cells. This is the first demonstration of methylation-dependent regulation of SF-1 in any mammalian tissue. These findings point to a new mechanism for targeting local estrogen biosynthesis in endometriosis.
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                Author and article information

                Contributors
                seantsai@mail.ncku.edu.tw
                Journal
                Reprod Med Biol
                Reprod. Med. Biol
                10.1111/(ISSN)1447-0578
                RMB2
                Reproductive Medicine and Biology
                John Wiley and Sons Inc. (Hoboken )
                1445-5781
                1447-0578
                23 July 2017
                October 2017
                : 16
                : 4 ( doiID: 10.1111/rmb2.2017.16.issue-4 )
                : 314-319
                Affiliations
                [ 1 ] Department of Physiology College of Medicine National Cheng Kung University Tainan Taiwan
                [ 2 ] Department of Obstetrics and Gynecology College of Medicine National Cheng Kung University Tainan Taiwan
                Author notes
                [*] [* ] Correspondence

                Shaw‐Jenq Tsai, Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

                Email: seantsai@ 123456mail.ncku.edu.tw

                Author information
                http://orcid.org/0000-0002-1648-974X
                http://orcid.org/0000-0002-3569-5813
                Article
                RMB212047
                10.1002/rmb2.12047
                5715896
                29259483
                d407e19e-4eda-438c-b459-ff69b0247fd8
                © 2017 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 09 May 2017
                : 27 June 2017
                Page count
                Figures: 4, Tables: 0, Pages: 7, Words: 4160
                Funding
                Funded by: Ministry of Science and Technology, Taiwan
                Award ID: MOST 104‐2320‐B‐006 ‐036 ‐MY3
                Categories
                Mini Review
                Mini Review
                Custom metadata
                2.0
                rmb212047
                October 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:04.12.2017

                dna methylation,endometriosis,epigenetics,histone modification,microrna

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