WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
PLoS One. 2013 Apr 17;8(4):e61658. doi: 10.1371/journal.pone.0061658. Print 2013.
DNA methyltransferases (DNMTs) are key regulators of DNA methylation and have crucial roles in carcinogenesis, embryogenesis and epigenetic modification. In general, DNMT1 has enzymatic activity affecting maintenance of DNA methylation, whereas DNMT3A and DNMT3B are involved in de novo methylation events. Although DNMT genes are well known in mammals including humans and mice, they are not well studied in avian species, especially the laying hen which is recognized as an excellent animal model for research on human ovarian carcinogenesis. Results of the present study demonstrated that expression of DNMT1, DNMT3A and DNMT3B genes was significantly increased, particularly in the glandular epithelia (GE) of cancerous ovaries, but not normal ovaries. Consistent with this result, immunoreactive 5-methylcytosine protein was predominantly abundant in nuclei of stromal and GE cells of cancerous ovaries, but it was also found that, to a lesser extent, in nuclei of stromal cells of normal ovaries. Methylation-specific PCR analysis detected hypermethylation of the promoter regions of the tumor suppressor genes in the initiation and development of chicken ovarian cancer. Further, several microRNAs, specifically miR-1741, miR-16c, and miR-222, and miR-1632 were discovered to influence expression of DNMT3A and DNMT3B, respectively, via their 3'-UTR which suggests post-transcriptional regulation of their expression in laying hens. Collectively, results of the present study demonstrated increased expression of DNMT genes in cancerous ovaries of laying hens and post-transcriptional regulation of those genes by specific microRNAs, as well as control of hypermethylation of the promoters of tumor suppressor genes.
DNA 甲基转移酶（DNMTs）是 DNA 甲基化的关键调节因子，在致癌作用、胚胎发生和表观遗传修饰中起着至关重要的作用。一般来说，DNMT1 具有影响 DNA 甲基化维持的酶活性，而 DNMT3A 和 DNMT3B 则参与从头甲基化事件。尽管 DNMT 基因在包括人类和小鼠在内的哺乳动物中广为人知，但在禽类中研究甚少，特别是产蛋母鸡，它被认为是研究人类卵巢癌发生的优秀动物模型。本研究结果表明，DNMT1、DNMT3A 和 DNMT3B 基因的表达显著增加，特别是在癌变卵巢的腺体上皮（GE）中，但在正常卵巢中则不然。与这一结果一致的是，免疫反应性 5-甲基胞嘧啶蛋白主要在癌变卵巢的基质和 GE 细胞的核中丰富，但也发现，在一定程度上，在正常卵巢的基质细胞的核中也有发现。甲基化特异性 PCR 分析检测到在鸡卵巢癌的发生和发展中，肿瘤抑制基因启动子区域的异常高甲基化。此外，还发现几种 microRNAs，特别是 miR-1741、miR-16c 和 miR-222 以及 miR-1632，分别通过其 3'-UTR 影响 DNMT3A 和 DNMT3B 的表达，这表明在产蛋母鸡中，它们的表达受到转录后调控。综上所述，本研究结果表明，产蛋母鸡癌变卵巢中 DNMT 基因表达增加，特定 microRNAs 对这些基因进行转录后调控，并控制肿瘤抑制基因启动子的异常高甲基化。
