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首页> 外文期刊>Reviews of Reproduction >Arginine methyltransferases mediate an epigenetic ovarian response to endometriosis
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Arginine methyltransferases mediate an epigenetic ovarian response to endometriosis

机译：精氨酸甲基转移酶介导卵巢对子宫内膜异位症的反应

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Endometriosis is associated with infertility and debilitating chronic pain. Abnormal epigenetic modifications in the human endometrium have recently been implicated in the pathogenesis of this condition. However, whether an altered epigenetic landscape contributes to pathological changes in the ovary is unknown. Using an established baboon endometriosis model, early-, and late-stage epigenetic changes in the ovary were investigated. Transcript profiling of key chromatin-modifying enzymes using pathway-focused PCR arrays on ovarian tissue from healthy control animals and at 3 and 15 months of endometriosis revealed dramatic changes in gene expression in a disease duration-dependent manner. Ingenuity Pathway Analysis indicated that transcripts for chromatin-remodeling enzymes associated with reproductive system disease and cancer development were abnormally regulated, most prominently the arginine methyltransferases CARM1, PRMT2, and PRMT8. Downregulation of CARM1 protein expression was also detected in the ovary, fully-grown oocytes and eutopic endometrium following 15 months of endometriosis. Sodium bisulfite sequencing revealed DNA hypermethylation within the PRMT8 promoter, suggesting that deregulated CpG methylation may play a role in transcriptional repression of this gene. These results demonstrate that endometriosis is associated with changes of epigenetic profiles in the primate ovary and suggest that arginine methyltransferases play a prominent role in mediating the ovarian response to endometriosis. Owing to the critical role of CARM1 in nuclear receptor-mediated transcription and maintenance of pluripotency in the cleavage stage embryo, our results suggest that epigenetic alterations in the ovary may have functional consequences for oocyte quality and the etiology of infertility associated with endometriosis.
机译：子宫内膜异位症与不孕症和使慢性疼痛衰弱有关。最近，人类子宫内膜中的异常表观遗传修饰与该病的发病机制有关。但是，尚不清楚表观遗传景观的改变是否有助于卵巢的病理变化。使用建立的狒狒子宫内膜异位症模型，研究卵巢的早期和晚期表观遗传学变化。在健康对照动物的卵巢组织上以及在子宫内膜异位症的3和15个月时，使用聚焦于途径的PCR阵列对关键染色质修饰酶进行转录谱分析，揭示了基因表达的显着变化，其依赖于疾病持续时间。独创性途径分析表明，与生殖系统疾病和癌症发展相关的染色质重塑酶的转录物受到异常调节，其中最主要的是精氨酸甲基转移酶CARM1，PRMT2和PRMT8。子宫内膜异位症15个月后，在卵巢，成年卵母细胞和异位子宫内膜中也检测到CARM1蛋白表达下调。亚硫酸氢钠测序显示PRMT8启动子内的DNA超甲基化，表明CpG甲基化失控可能在该基因的转录抑制中起作用。这些结果表明，子宫内膜异位症与灵长类卵巢中表观遗传学特征的改变有关，并表明精氨酸甲基转移酶在介导卵巢对子宫内膜异位症的反应中起着重要作用。由于CARM1在核受体介导的转录和卵裂期多能性的维持中起关键作用，我们的结果表明，卵巢中的表观遗传学改变可能对卵母细胞质量和与子宫内膜异位症相关的不孕症的病因具有功能性影响。

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