Aberrant DNA methylation status of endometriosis: Epigenetics as the pathogenesis, biomarker and therapeutic target

Abstract

Endometriosis, a common, benign, estrogen-dependent disease affecting 3-10% of women of reproductive age, is characterized by the ectopic growth of endometrial tissue that is found primarily in the peritoneum, ovaries and rectovaginal septum. Recently, endometriosis has been alternatively described as an immune disease, a genetic disease and a disease caused by exposure to environmental factors, in addition to its usual description as a hormonal disease. In addition, accumulating evidence suggests that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis. Epigenetic alterations reported to date in endometriosis include the genomic DNA methylation of progesterone receptor-B, E-cadherin, homeobox A10, estrogen receptor-β, steroidogenic factor-1 and aromatase. Aberrant expression of DNA methyltransferases, which attach a methyl group to the 5-carbon position of cytosine bases in the CpG island of the promoter region and silence the corresponding gene expression, has also been demonstrated in endometriosis. This review summarizes the recent studies on the aberrant DNA methylation status and aberrant expression of DNA methyltransferases, which regulate DNA methylation, in endometriosis. We also discuss the recent information on the diagnostic and therapeutic implications of epigenetic alterations occurring in endometriosis.

Methylation status and protein expression of RASSF1A in endometriosis

“…The epigenetic mechanisms represent a heritable dynamic and reversible means of modulating gene expression. The reversible nature of epigenetic aberrations is an important characteristic, since it allows us to search for appropriate pharmacological treatments, or 'epigenetic therapies' (25). In a number of studies it was demonstrated that RASSF1A expression was significantly increased or markedly upregulated in a number of types of cancer, including ovarian cancer and endometrial carcinoma, after treatment with 5-aza-DC (26)(27)(28).…”

Epigenetic background of the most common non-oncologic gynecological diseases

“…Mindegyik DNMT-enzim génje endometriosisos sejtekben hipermetilálódik, ami fokozott génexpresszió-hoz vezet. Miután e gének működése szoros kapcsolatban van a kromatinszerveződés folyamataival is, így mű-ködésváltozásaik két epigenetikai mechanizmusrendszer (DNS-metiláció, kromatinszerveződés) működésével is összefüggést mutatnak [36].…”

“…Miközben a csökkenés mindkét progeszteronreceptortípust érinti, egyszersmind a PR-A:PR-B arány megváltozása is jellegzetes, az endometriosisra jellemző jelenség. Néhány évvel ezelőtt kutatási eredmények szá-moltak be a PR-B génjének hipermetilációjáról endometriosisban, amely downreguláció révén a progeszteronhatás felfüggesztődését okozza [36,40]. Wu vizs gálati eredményei azt is felvetették, hogy a PR-B génjének hipermetilációja a krónikus gyulladás kapcsán TNF-alfa hatására jön létre, vagyis az epigenetikai vál-tozás stimulációját maga a gyulladás jelenti [41].…”

“…Ez utóbbi mechanizmus különösen fontosnak tűnik az endometriosis patomechanizmusában [36]. Az endometrioticus gócokban az aromatáz aktivitás révén folyamatosan zajló ösztrogénprodukció a kórkép progreszszióját okozza.…”

Epigenetic: A new approach to etiology of infertility

“…In addition, estrogen-β receptor, steroidogenic-1factor and aromatase also underwent hypomethylation. 46 Inhibition of the E-cadherin expression due to hypermethylation causes disruption of cell adhesion, thus inducing invasion and metastasis of endometrial cells. HOXA10 genes in humans is expressed in the endometrium that is regulated by estrogen and progesterone.…”