Masao Izawa1 , Fuminori Taniguchi1 and Tasuku Harada1
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan
There is accumulating evidence supporting the concept that endometriosis is a disease associated with an epigenetic disorder. Epigenetics is one of the most expanding fields in the current biomedical research. The word “epigenetics” refers to the study of mitotically and/or meiotically heritable changes in gene expression that occur without changes in the DNA sequence. The disruption of such changes (epigenetic aberration or disorder) underlies a wide variety of pathologies. Epigenetic regulation includes DNA methylation and histone modifications and is responsible for a number of gene transcriptions associated with chromatin modifications that distinguish the states of diseases. As an introduction, we summarize our findings of epigenetic disorder in endometriotic cells and then overview recent studies focused on DNA methylation in endometriosis. We describe our recent challenge and advanced studies from other laboratories using genome-wide (GW) analysis. Finally, we refer to environmental factors as a potential background of epigenetic disorder in endometriosis.
Aberrant DNA methylationAberrant histone modificationAberrant transcriptionEpigenetic disorder
8.1 Why Epigenetics in Endometriosis?
Epigenetics is one of the most promising and expanding fields in the current biomedical research. The word “epigenetics” refers to the study of mitotically and/or meiotically heritable changes in gene expression that occur without changes in the DNA sequence . The disruption of such changes (epigenetic aberration or disorder) underlies a wide variety of pathologies including cancer [2, 3]. Epigenetic regulation includes DNA methylation and histone modifications [4, 5] and is responsible for a number of gene transcriptions associated with chromatin modifications that distinguish the various cell types and the states of diseases. Cancer and many other diseases show aberrant epigenetic regulation . In terms of DNA methylation, cancer cells show genome-wide (GW) hypomethylation and site-specific hypermethylation of promoter CpG islands . This may lead to transcriptional silencing and aberrant transcription from incorrect transcription start sites . In addition, a recent study comparing colorectal cancer tissue with its normal counterpart suggests changes at the CpG island shores . In normal cells, CpG islands and CpG island shores are under the control of physiological methylation, allowing normal gene transcription.
There is accumulating evidence supporting the concept that endometriosis is an epigenetic disease . The concept of aberrant DNA methylation in endometriosis is expanding . Here we describe how the field of epigenetics is reshaping the current thinking about endometriosis. Firstly, we present our study shedding light on aberrant aromatase expression in endometriosis from the viewpoint of epigenetic disorder and then summarize recent advances in endometriosis research using the epigenetic approach. We subsequently describe the advanced technologies of GW methylation analysis and GW association study (GWAS) in endometriosis research. Finally, we refer to environmental factors as a potential background of epigenetic disorder in endometriosis.
8.2 Estrogen Environment in Endometriosis
Endometriotic tissue growth depends on ovarian steroids; thus, medical treatments aim to reduce ovarian steroidogenesis. Continuous exposure to GnRH agonist results in desensitization or downregulation of GnRH receptors leading to reduced serum gonadotropin levels and reduced ovarian hormone production. Treating endometriosis with GnRH agonist reduces both the number of observable endometriotic implants and the frequency and severity of associated pain [10, 11]. Likewise, inhibition of estrogen production by progestins or aromatase inhibitors reduces endometriotic lesions and clinical symptoms . Three major sites for estrogen production are recognized in women with endometriosis: (a) de novo synthesis in the ovary, (b) an intrinsic system that depends on aromatase, which converts circulating androstenedione to estradiol (intracrine) in the skin and adipose tissue, and (c) a de novosystem and an intracrine system in endometriotic tissues [13, 14]. Among these sites, local estrogen production, which depends on aberrantly expressed aromatase in endometriotic implants, plays an important role in the pathophysiology of endometriosis [15–17]. Local estrogen production by these implants may contribute to the progression of endometriosis even under the hypoestrogenic environment produced by GnRH agonist exposure .
8.2.1 Aromatase Upregulation in Endometriosis
Aromatase, an enzyme that catalyzes the conversion of androgens to estrogens, is a key molecule for estrogen production. Aromatase is encoded by a single-copy gene CYP19 on chromosome 15q21. CYP19 expression is regulated in a tissue-specific manner, in which alternative usage of multiple promoters with each unique cis-acting element has been known . Therefore, identifying the promoter usage becomes the first step in understanding the molecular background of aromatase expression in specific tissues. Bulun et al. previously reported that promoter II is the most potent promoter functioning in endometriotic cells from endometrioma . In addition to promoter II, we recently demonstrated that two proximal promoters, I.3 and I.6, are used additionally in endometriotic cells . At the same time, we observed that aromatase transcription in endometrial cells was at a marginal level depending on the same 3 promoters as those of endometriotic cells . From these observations, we hypothesized that the upregulation of aromatase gene in endometriotic cells may be an epigenetic disorder, since hypermethylation of promoter region in tumor suppressor gene associated with gene silencing has been known.
8.2.2 DNA Demethylation and Aromatase Upregulation in Endometriotic Cells
An epigenetic disorder may lead to the aromatase upregulation in endometriotic cells. We challenged this hypothesis: after treating endometrial cells with 5-aza-deoxycytidine (5-aza-dC, competitive inhibitor for DNA methyltransferase) for 96 h, aromatase transcription was markedly upregulated in the cells (Fig. 8.1). This is the first demonstration that epigenetic modification enhances aromatase mRNA expression . The enhanced aromatase mRNA expression was dependent on the same promoters as those in endometriotic cells (Fig. 8.2). When the effect of trichostatin A (TSA), instead of 5-aza-dC, on aromatase mRNA expression was examined, we observed little effect, suggesting that one of the major factors that suppresses aromatase mRNA expression in endometrial cells is the methylation of aromatase gene and/or its trans-acting factor gene. Alternatively, the observation suggests that a disorder of a putative methylation-dependent suppression mechanism may lead to the upregulation of aromatase mRNA expression in endometriotic cells.
Aromatase mRNA induction in response to 5-aza-dC in endometrial cells. (a) RT-PCR: lane 1, untreated control, lanes 2 and 3, treated with 5-aza-dC, and lanes 4 and 5, treated with TSA. (b) Semiquantitative analysis
Promoter usage of aromatase mRNA expression. Left: 5-aza-dC-treated endometrial cells. Right: endometriotic cells
8.2.3 Hypomethylated CpG Island Within the Aromatase Gene in Endometriotic Cells
We searched for the unmethylated CpG locus within the aromatase gene in endometriotic cells . We predicted a CpG island at approximately 20 kb upstream from the end of exon II (Fig. 8.3). In endometriotic cells, the CpG sequence was hypomethylated, while in endometrial cells, the upstream half was hypermethylated and recognized by the methyl-CpG binding proteins, MBD1 and MeCP2 . The downstream half was hypomethylated in both endometrial and endometriotic cells. Because the CpG sequence is located at the promoter-distal region, we speculate that the sequence may act as a cis-acting element under the control of methylation.
A hypomethylated CpG island at 20 kb upstream from the end of exon II in endometriotic cells
8.3 Nuclear Receptor Genes Under Epigenetic Aberration in Endometriosis
Estrogen receptor (ER) plays pivotal roles in the pathogenesis and progression of endometriosis. Earlier studies have focused on the expression of ERα as well as ERβ in the eutopic endometrium and in endometriotic lesions. Simultaneous expression of ERα and ERβ indicates that the estrogen action might be transmitted in a cooperative manner [20, 21]. In contrast to the high ERα/ERβ expression ratio in the eutopic endometrium, a lower expression of ERα and a markedly higher expression of ERβ in ovarian endometriomas have been reported [22, 23]. The higher ERβ expression in endometriotic tissue may depend on the hypomethylation of the ERβ-promoter region . The increased ERβ expression in endometriotic tissues may suppress ERα expression .
8.3.1 ERβ Gene: Hypomethylation and Upregulation
That the development and progression of endometriosis depends on estrogen is well known [26, 27]. ERα and ERβ function as transcription factors and are believed to play key roles in tissue growth of endometrium and endometrioma [22, 23]. Previous studies demonstrated markedly higher levels of ERβ and lower levels of ERα in endometriotic tissues and endometriotic stromal cells [21–23]. Differences in the ERα/ERβ ratio between endometriotic and endometrial stromal cells are suggested to have important functional implications . Recently, Xue et al.  demonstrated that the ERβ promoter is hypomethylated in endometriotic cells. Hypomethylation caused the higher expression of ERβ gene in endometriotic cells, while hypermethylation silenced the expression in endometrial cells. Treatment with a demethylating agent significantly increased ERβ mRNA expression in endometrial cells. They proposed that enhanced ERβ transcription in endometriotic cells takes over the ERα promoter activity, thus favoring the suppression of ERα levels .
8.3.2 Progesterone Receptor (PR) Gene: Hypermethylation and Downregulation
Progesterone induces differentiation of endometrial stromal cells to decidualized cells and glandular epithelial cells to the secretory phenotype. Representative molecular markers of progesterone action include increased production of epithelial glycodelin and stromal prolactin in the endometrium [28, 29]. Progesterone resistance is known as a feature in some endometriosis and can be attributed to the low level of PR in endometriotic tissue [30–32]. PR-A and PR-B forms are expressed in the stromal and epithelial components of the endometrium . In the endometrium, expressions of PR-A and PR-B are progressively upregulated during the proliferative phase to their highest level immediately before ovulation, and diminish thereafter, suggesting that estradiol stimulates PR expression . PR level may be related to the responsiveness to progesterone in patients [33, 34]. Wu et al.  have shown that the promoter region of PR-B is hypermethylated in endometriosis, which may lead to the PR-B downregulation. They recently showed that prolonged stimulation of TNF-α induced partial methylation in the promoter region of PR-B associated with decreased expression of PR-B in an immortalized epithelial-like endometriotic cell line . This seems to provide evidence that phenotypic changes in endometriosis, such as chronic inflammation associated with increased production of proinflammatory cytokines, may cause epigenetic aberrations leading to changes in gene expression .
8.4 Other Genes Under Epigenetic Aberration in Endometriosis
8.4.1 Steroidogenic Factor-1 (SF-1) Gene: Hypomethylation and Upregulation
SF-1 is a transcriptional factor essential for the activation of multiple steroidogenic genes for estrogen biosynthesis, such as the genes for steroid acute regulatory (StAR) and aromatase [38–40]. SF-1 is usually undetectable in eutopic endometrial cells . It has been demonstrated that SF-1 mRNA and protein levels in endometriotic cells were significantly higher than those in eutopic endometrial cells [40, 41]. Xue et al. identified a classical CpG island at the promoter region of the SF-1 gene and showed that the SF-1 promoter has increased methylation in eutopic endometrial cells . In endometrial cells, the silencer-type transcription factor MBD2 is recruited to the methylated SF-1 promoter and prevents its interaction with transcriptional activators, resulting in silencing of the SF-1 gene. On the other hand, the SF-1 promoter is hypomethylated in endometriotic cells. Steroidogenic factor-2 (SF-2), a transcription factor highly expressed in endometriotic tissues, binds to the unmethylated SF-1 promoter and activates its transcription in endometriotic cells . The SF-1 expression is under epigenetic control that permits the binding of activator complexes to the SF-1 promoter [41, 42]. SF-1 expression in endometriosis may enhance aromatase expression. Treatment with a demethylating agent has been shown to increase SF-1 mRNA levels in eutopic endometrial cells .
8.4.2 E-Cadherin Gene: Hypermethylation and Downregulation
Downregulation of E-cadherin, a known metastasis-suppressor protein in epithelial tumor cells , has been shown in endometriotic cells . In two immortalized endometriotic cell lines, the E-cadherin gene was found to be hypermethylated at the promoter region, and treatment with a histone deacetylase inhibitor TSA induced expression . Interestingly, the increased promoter methylation of the E-cadherin gene during aging has been demonstrated .
8.4.3 HOXA10 Gene: Hypermethylation and Downregulation
HOXA10 has been expressed in the endometrium, and its expression is under the control of estrogen and progesterone [46–48]. The roles in endometrial development during the menstrual cycle and in establishing uterine receptivity have been suggested [47, 48]. In women with endometriosis, HOXA10 expression is significantly decreased in the eutopic endometrium during the secretory phase, indicating functional defects in uterine receptivity [47, 49]. The promoter region of HOXA10 gene was found to be hypermethylated in the eutopic endometrium from women with endometriosis . As promoter hypermethylation has been suggested as an epigenetic marker of gene silencing, the promoter hypermethylation may be related to the HOXA10 downregulation in the eutopic endometrium of women with endometriosis .
8.5 Genome-Wide (GW) Profiling of DNA Methylation and GW Association Study (GWAS) in Endometriosis
Methylation of DNA provides a layer of epigenetic controls that has important implications for diseases including endometriosis. There has been a revolution in DNA methylation analysis technology. Analyses can now be performed on a genome-scale and entire methylomes can be characterized at single-base-pair resolution . In endometriosis, a number of aberrant gene expressions have been demonstrated [52, 53]. These aberrations may be related to aberrant DNA methylations. However, it is unknown whether global alterations in DNA methylation patterns occur in endometriosis and to what extent they are involved in its pathogenesis. A whole-genome scanning of CpG methylation status in more than 25,000 promoters has been conducted previously . The results showed highly similar methylation profiles between endometrium and endometriotic lesions. Recently, a new generation of genome-wide DNA methylation BeadChip array including 485,577 CpGs (Infinium HumanMethylation450 BeadChip Array) has been developed [55, 56]. The array covers more than 99 % of human genes and 96 % of CpG islands. Using the array, we recently identified 1,811 CpGs (0.38 %) differentially methylated not only in the promoter region but also in promoter-distal CpGs (Fig. 8.4) . Among them, 954 CpGs (52.7 %) were hypermethylated, while 857 CpGs (47.3 %) were hypomethylated in endometriotic cells. The results indicate that the overall methylation profile in endometriotic cells was highly similar to that in endometrial cells. The observation supports the retrograde menstruation theory by Sampson  for the pathogenesis of endometriosis. It is important to note that the CpGs hypomethylated or hypermethylated in endometriotic cells were demonstrated not always in promoter CpG islands. These observations show a facet of epigenetic disorder in endometriosis.
Differentially methylated CpGs in endometriotic cells (a) CpGs, which show more than 10-fold difference, were extracted (b) the classification
Through a GWAS and a replication study using a total of 1,907 Japanese individuals with endometriosis and 5,292 controls, a significant association of endometriosis with rs10965235 (P = 5.57 × 10(−12), odds ratio = 1.44), which is located in CDKN2BAS on chromosome 9p21, encoding the cyclin-dependent kinase inhibitor 2B antisense RNA was identified . The findings suggest that these regions are susceptible loci for endometriosis. A GWAS was performed using two case-control cohorts genotyped with the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0 in Japanese women with endometriosis . A GWAS in 3,194 individuals with surgically confirmed endometriosis and 7,060 controls from Australia and the UK was conducted . The strongest association signal was reported on 7p15.2 (rs12700667) for endometriosis. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10.
8.6 Epigenetic Aberrations and Environmental Factors in Endometriosis
The known epigenetic modifications are DNA methylation and histone modifications, including methylation, acetylation, ubiquitylation, and phosphorylation . The functional and biological significance of the epigenetic alterations accumulate over a life span. The earliest studies found a pattern of low global DNA methylation levels in aged mammalian tissues . A recent monozygotic (MZ) twin study showed a line of evidence that epigenetic variants accumulate during aging independently of the genetic sequence . The study tested the epigenetic contribution to twin discordance and elucidated the effect of environmental characteristics on gene function. The results revealed that epigenetic difference between siblings is associated with phenotypic discordance, which might be attributed to an unshared environment.
8.6.1 Effect of Environmental Factors on Epigenome
The association between environmental factors and phenotypic discordance within MZ twins has been noticed . However, little is known about the molecular basis by which environmental factors influence gene functions . Typical examples are the abnormal intrauterine environment associated with epigenetic downregulation of genes [66, 67] and the maternal diet associated with the DNA methylation profile of offspring [68–70]. Gene function and chromatin structure can be modulated by environmental factors [71, 72]. In response to a methyl-deficient diet, a significant decrease in repressive dimethyl-H3K9 associated with the upregulation of targeted gene was demonstrated in mice . Environmental factors, including endocrine disrupting chemicals, may affect the epigenome leading to the onset of endometriosis in utero. There might be epigenetic changes during ontogenic development [74, 75].
8.6.2 DNA Methylation, Aging, and Endometriosis
The great fidelity with which DNA methylation patterns in mammals are inherited after each cell division is ensured by the DNA methyltransferases (DNMTs). However, the aging cell undergoes a DNA methylation drift. Early studies showed that global DNA methylation decreases during aging in many tissue types . The loss of global DNA methylation during aging is probably mainly the result of the passive demethylation of DNA as a consequence of a progressive loss of DNMT activity . Several specific regions of the genomic DNA become hypermethylated during aging . Methylation of promoter CpG islands in nontumorigenic tissues has been reported for several genes, including ER . Interestingly, genes with increased promoter methylation during aging include the E-cadherin gene , which is downregulated and hypermethylated in endometriotic cells . Aberrant methylation of CpG islands in 5′ promoters has been suggested to be associated with transcriptional silencing or upregulation in endometriosis [24, 33, 36, 50]. Recent GW methylation studies suggest that tissue- and cell-type-specific methylation is present only in a small percentage of CpG islands in 5′ promoters, while a far greater proportion of CpG island methylation is across gene bodies [78, 79]. In addition, functionally different types of DNA modification, methylation, and hydroxymethylation have been identified [78, 80]. Therefore, methylation of CpG islands in 5′ promoters alone may not be a major player in the aberrant gene expression.
8.6.3 Histone Modification, Aging, and Endometriosis
Histone modifications have a defined profile during aging. For example, the trimethylation of H4-K20, which is enriched in differentiated cells , increases with age [82, 83] and decreases in cancer cells [83–87]. A decrease in the histone trimethylation has been observed in the liver after the long-term treatment with the hepatocarcinogen tamoxifen . The loss of trimethylated H4-K20 in cancer can be caused by the loss of expression of the H4-K20-specific methyltransferase Suv4-20h . Although approximately 100 histone methyltransferases and demethylases have been identified in human genome, only a subset of histone methyltransferase inhibitor is in clinical trials for cancer treatment .
Acetylation levels of histones are controlled by a balance between histone acetyltransferases and histone deacetylases (HDACs). Histone acetyltransferases transfer acetyl groups from acetyl-CoA to lysine residues on the amino-terminal region of histones and activate gene transcription. Conversely, HDACs restore the positive charge on lysine residues by removing the acetyl groups and prevent transcription. HDACs comprise large multiprotein complexes that target promoter sites through their interaction with sequence-specific transcription sites. HDAC inhibitors (HDACIs) can inhibit cell proliferation, induce cell differentiation and cell cycle arrest, and stimulate apoptosis of various cell types . Hyperacetylation of histones H3 and H4 is often associated with activated transcription, and hypoacetylation of histones H3 and H4 correlates with transcriptional silencing or repression . Kawano et al.  recently demonstrated that treatment with HDACIs induced the accumulation of acetylated histones associated with some cell cycle-related gene expressions in endometriotic cells. The advanced human epigenome projects [51, 93] may provide further insight into understanding epigenetic aberrations in endometriosis.
Epigenetics is one of the most promising and expanding fields in the current biomedical research of diseases including endometriosis. Most important is its translational application. One of the immediate questions to be clarified in endometriosis is which genome is under epigenetic aberration. Here we focused mostly on DNA methylation and reviewed current epigenetics studies in endometriosis.
Epigenetics is currently expanding from DNA methylation to histone modifications (Fig. 8.5) . The development of high-throughput technologies including GW analysis associated with next-generation sequencer is accelerating the study of epigenetic aberration in endometriosis. Using the epigenetic concept as a tool, new diagnostic marker or therapy may be developed to overcome serious problems in patients with endometriosis.
Organization and composition of epigenome. (a) A “beads-on-a-string” chromatin fiber includes nucleosome cores connected by linker DNA and linker histone H1. Me: methyl group. (b) The distribution of DNA methylation and a small subset of histone markings, linker histones, and core histone variants represent a different regulation at active promoters, gene bodies, and enhancers (top) as compared to silenced and repressed chromatin (bottom)
This work was supported in part by Grants-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (Nos. 22591824 and 18591800 to M.I.).
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