Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin
Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin
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DOI：
10.1038/sj.onc.1209362
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发表时间：
2006-06-01
期刊：
影响因子：
8
通讯作者：
Okamoto, K.
中科院分区：
文献类型：
--
作者：
Kawakami, T.;Zhang, C.;Okamoto, K.
全基因组表观遗传模式。在发育的关键阶段，阳离子在调节基因组功能中起着至关重要的作用。特别是，DNA甲基化在生殖细胞和着床前胚胎的全基因组水平上被重新编程，尽管它在体细胞中相对稳定。在这个重编程过程中，基因组去甲基化，并在发育后期重新甲基化。男性生殖细胞中DNA甲基化的重编程尚未得到充分的研究。睾丸生殖细胞瘤（tgct）具有多能性，并表现出从生殖细胞到胚胎细胞和体细胞分化的蛋白质组织学特征。这些特性使TGCT在DNA重编程方面成为研究生殖细胞发育和配子体发生的独特模型。为了深入了解tgct的表观遗传动力学，我们对tgct与睾丸恶性淋巴瘤的H19和IGF2差异甲基化区（DMRs）进行了全面分析。在本研究中，我们发现H19上游启动子和ctcf结合位点的甲基化印记在半瘤性和非半瘤性tgct中都被完全消除，而在睾丸淋巴瘤中观察到差异甲基化。在恶性转化的tgct中也观察到甲基化印记的消除。我们发现H19上游的启动子和ctcf结合位点的双等位基因非甲基化是必需的，但对于tgct中H19的双等位基因表达并不充分。这些数据表明，除甲基化外，其他因素也参与了tgct中印迹基因的转录调控。目前的数据表明，来自其他体细胞起源的肿瘤的tgct在H19/IGF2的核心印记区域携带独特的表观遗传谱。这些数据还表明，半细胞瘤和非半细胞瘤的tgct携带的甲基化谱与胎儿生殖细胞相似，但与成人生殖细胞不同，这表明tgct起源于胎儿生殖细胞。
Genome-wide epigenetic modi. cation plays a crucial role in regulating genome functions at critical stages of development. In particular, DNA methylation is known to be reprogrammed on a genome-wide level in germ cells and in preimplantation embryos, although it is relatively stable in somatic cells. In this reprogramming process, the genome becomes demethylated, and methylated de novo during later stages of development. Reprogramming of DNA methylation in male germ cells has not been fully investigated. Testicular germ cell tumors (TGCTs) possess a pluripotential nature and display protean histology from germ cells to embryonal and somatic cell differentiation. These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming. In order to obtain an insight into the epigenetic dynamics of TGCTs, we conducted a comprehensive analysis of differential methylated regions (DMRs) on H19 and IGF2 in TGCTs compared with testicular malignant lymphomas. In the present study, we show that methylation imprint at the promoter and CTCF-binding site upstream of H19 was completely erased in both seiminomatous and non-seminomatous TGCTs, whereas differential methylation was observed in testicular lymphomas. The erasure of methylation imprint was also observed in TGCTs with malignant transformation. We found biallelic unmethylation at the promoter and the CTCF-binding site upstream of H19 is required, but not sufficient for the biallelic expression of H19 in TGCTs. These data suggest that factors other than methylation contribute to transcriptional regulation of imprinted genes in TGCTs. The present data have shown that TGCTs carry distinctive epigenetic profiles at the core-imprinting domain of H19/IGF2 from other neoplasms of somatic cell origin. The data also suggest that both seminomatous and nonseminomatous TGCTs carry methylation profiles similar to fetal germ cells, but not adult germ cells, indicating the origin of TGCTs as fetal germ cells.