Cell type-specific DNA methylation patterns in the human breast
Cell type-specific DNA methylation patterns in the human breast
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DOI：
10.1073/pnas.0805206105
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发表时间：
2008-09-16
影响因子：
11.1
通讯作者：
Polyak, Kornelia
中科院分区：
文献类型：
--
作者：
Bloushtain-Qimron, Noga;Yao, Jun;Polyak, Kornelia
细胞身份和分化由表观遗传程序决定。这些程序在正常人乳腺上皮中的特征以及它们与干细胞中程序的相似性尚不清楚。为了开始研究这些问题，我们利用甲基化特异性数字核型分析（MSDK）和基因表达系列分析（SAGE）分析了乳腺上皮细胞不同亚群的DNA甲基化和基因表达谱。我们确定了离散的细胞类型和分化状态特异性DNA甲基化及基因表达模式，这些模式在一部分乳腺癌中得以维持，并与临床相关的肿瘤亚型相关。CD44⁺细胞是甲基化程度最低的，并且高度表达几种具有已知干细胞功能的转录因子，包括HOXA10和TCF3。通过MSDK分析用于比较的未分化人类胚胎干细胞（ES）相比，在经BMP4处理的细胞中，许多这些基因也是低甲基化的。进一步凸显了胚胎细胞和乳腺上皮细胞表观遗传程序的相似性，相对于分化程度更高的CD24⁺细胞，在CD44⁺细胞中高度表达的基因在ES细胞中显著富集于Suz12靶点。FOXC1是在CD44⁺细胞中低甲基化且高度表达的转录因子之一，其表达在分化的乳腺上皮细胞中诱导出祖细胞样表型。这些数据表明，受表观遗传控制的转录因子在调节乳腺上皮细胞表型中起关键作用，并暗示了定义祖细胞特征的表观遗传程序之间的相似性。
Cellular identity and differentiation are determined by epigenetic programs. The characteristics of these programs in normal human mammary epithelium and their similarity to those in stem cells are unknown. To begin investigating these issues, we analyzed the DNA methylation and gene expression profiles of distinct subpopulations of mammary epithelial cells by using MSDK (methylation-specific digital karyotyping) and SAGE (serial analysis of gene expression). We identified discrete cell-type and differentiation state-specific DNA methylation and gene expression patterns that were maintained in a subset of breast carcinomas and correlated with clinically relevant tumor subtypes. CD44+ cells were the most hypomethylated and highly expressed several transcription factors with known stem cell function including HOXA10 and TCF3. Many of these genes were also hypomethylated in BMP4-treated compared with undifferentiated human embryonic stem (ES) cells that we analyzed by MSDK for comparison. Further highlighting the similarity of epigenetic programs of embryonic and mammary epithelial cells, genes highly expressed in CD44+ relative to more differentiated CD24+ cells were significantly enriched for Suz12 targets in ES cells. The expression of FOXC1, one of the transcription factors hypomethylated and highly expressed in CD44+ cells, induced a progenitor-like phenotype in differentiated mammary epithelial cells. These data suggest that epigenetically controlled transcription factors play a key role in regulating mammary epithelial cell phenotypes and imply similarities among epigenetic programs that define progenitor cell characteristics.