Wide-ranging DNA methylation differences of primary trophoblast cell populations and derived cell lines: implications and opportunities for understanding trophoblast function.
Wide-ranging DNA methylation differences of primary trophoblast cell populations and derived cell lines: implications and opportunities for understanding trophoblast function.
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DOI：
10.1093/molehr/gar005
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发表时间：
2011-06
影响因子：
4
通讯作者：
Saffery R
中科院分区：
文献类型：
--
作者：
Novakovic B;Gordon L;Wong NC;Moffett A;Manuelpillai U;Craig JM;Sharkey A;Saffery R
与原代滋养层细胞长期培养相关的困难已被证明是其功能表征的主要障碍。为了绕过这个问题，多年来已经使用各种不同的方法建立了几个模型细胞系。其中包括源于妊娠肿瘤的细胞系，或原始滋养层细胞的转化/永生化。由于它们的起源、基因表达谱和体外行为不同，不同的模型系已被用于研究滋养细胞生物学的特定方面。然而，总的来说，功能差异背后的分子机制仍不清楚。在这项研究中，我们对最初的妊娠早期滋养层细胞和七个常用的滋养层细胞系的基因组规模的DNA甲基化进行了分析，试图确定这些细胞中受表观遗传修饰差异调节的功能通路。我们发现，在四个绒毛膜癌(CCA)来源的细胞系和转化的HTR-8/SVneo细胞中，DNA启动子甲基化水平普遍增加，包括几个在人类癌症中常见的基因的超甲基化，而与免疫反应、细胞形态、发育和迁移相关的基因在不同细胞群中的甲基化也存在差异。有趣的是，CCA来源的细胞系表现出更类似于无关实体癌而不是未转化滋养层细胞的整体甲基化特征，突出了异常DNA甲基化在CCA发育和/或长期培养中的作用。对CCA细胞和细胞滋养层细胞的DNA甲基化和基因表达的比较表明，DNA甲基化对整体表达谱有显著贡献，很可能是不同来源细胞之间潜在的功能差异。这些数据突出了原代滋养层细胞和细胞模型在支持广泛细胞功能的途径中表观遗传状态的差异，为未来不同细胞群体的功能研究提供了有价值的候选途径。这项研究还证实了在解释体外操纵这类通路所产生的数据时需要谨慎。
Difficulties associated with long term culture of primary trophoblasts have proven to be a major hurdle in their functional characterization. In order to circumvent this issue, several model cell lines have been established over many years using a variety of different approaches. These include lines derived from gestational tumors, or transformation/immortalization of primary trophoblast cells. Due to their differing origins, gene expression profiles, and behavior in vitro, different model lines have been utilized to investigate specific aspects of trophoblast biology. However, generally speaking, the molecular mechanisms underlying functional differences remain unclear. In this study, we profiled genome-scale DNA methylation in primary first trimester trophoblast cells and seven commonly used trophoblast-derived cell lines in an attempt to identify functional pathways differentially regulated by epigenetic modification in these cells. We identified a general increase in DNA promoter methylation levels in four choriocarcinoma (CCA)-derived lines and transformed HTR-8/SVneo cells, including hypermethylation of several genes regularly seen in human cancers, while other differences in methylation were noted in genes linked to immune responsiveness, cell morphology, development and migration across the different cell populations. Interestingly, CCA-derived lines show an overall methylation profile more similar to unrelated solid cancers than to untransformed trophoblasts, highlighting the role of aberrant DNA methylation in CCA development and/or long term culturing. Comparison of DNA methylation and gene expression in CCA lines and cytotrophoblasts revealed a significant contribution of DNA methylation to overall expression profile, most likely underlying functional variation between cells of different origin. These data highlight the variability in epigenetic state between primary trophoblasts and cell models in pathways underpinning a wide range of cell functions, providing valuable candidate pathways for future functional investigation in different cell populations. This study also confirms the need for caution in the interpretation of data generated from manipulation of such pathways in vitro.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.8
作者：
Aplin, JD;Straszewski-Chavez, SL;Knöfler, M
通讯作者：
Knöfler, M
David Gene功能分类工具：一种以生物模块为中心的新型算法，可在功能上分析大基因列表。
影响因子：
12.3
作者：
Huang, Da Wei;Sherman, Brad T;Tan, Qina;Collins, Jack R;Alvord, W Gregory;Roayaei, Jean;Stephens, Robert;Baseler, Michael W;Lane, H Clifford;Lempicki, Richard A
通讯作者：
Lempicki, Richard A
影响因子：
2.7
作者：
Arima, Takahiro;Hata, Kenichiro;Wake, Norio
通讯作者：
Wake, Norio
影响因子：
3.8
作者：
Burleigh, D. W.;Kendziorski, C. M.;Golos, T. G.
通讯作者：
Golos, T. G.