Epigenetic regulation of normal human mammary cell type-specific miRNAs
Epigenetic regulation of normal human mammary cell type-specific miRNAs
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DOI：
10.1101/gr.123935.111
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发表时间：
2011-12-01
期刊：
影响因子：
7
通讯作者：
Futscher, Bernard W.
中科院分区：
文献类型：
--
作者：
Vrba, Lukas;Garbe, James C.;Futscher, Bernard W.
表观遗传机制是细胞类型特异性基因的重要调节因子，包括miRNAs。为了确定受表观遗传机制调控的特定细胞类型的miRNAs，我们对三对人乳腺上皮细胞(HMEC)和人乳腺成纤维细胞(HMF)的miRNA表达和表观遗传状态进行了全局分析，这三对细胞代表了典型地存在于给定器官中的两种分化细胞类型，每种细胞都具有不同的表型和表观类型。虽然miRNA的表达和表观遗传状态在给定的细胞类型中显示出很强的个体间一致性，但几乎10%的表达的miRNA表现出与其启动子的表观遗传状态相关联的细胞类型特定的表达模式。组织特异性miRNA基因在非表达细胞中受到DNA甲基化(38%)和H3K27me3(58%)的表观遗传抑制，仅有一小部分miRNAs(21%)显示双重表观遗传抑制，其中DNA甲基化和H3K27me3同时存在于其启动子，如MIR10A和MIR10B。紧密相关的miRNA基因家族的单个miRNA簇都可以通过相同或互补的表观遗传机制显示细胞类型特异性的抑制，例如miR200家族和MIR205，其中成纤维细胞通过DNA甲基化抑制MIR200C/141，通过H3K27me3抑制MIR200A/200B/429，通过DNA甲基化和H3K27me3抑制MIR205。由于我们发现的许多表观遗传调控的miRNAs的解除调控与癌症等疾病过程有关，因此可以预测，表观遗传调控机制的妥协对这一过程非常重要。总体而言，这些结果强调了表观遗传调控在控制正常细胞类型特异性miRNA表达方面的重要性。
Epigenetic mechanisms are important regulators of cell type-specific genes, including miRNAs. In order to identify cell type-specific miRNAs regulated by epigenetic mechanisms, we undertook a global analysis of miRNA expression and epigenetic states in three isogenic pairs of human mammary epithelial cells (HMEC) and human mammary fibroblasts (HMF), which represent two differentiated cell types typically present within a given organ, each with a distinct phenotype and a distinct epigenotype. While miRNA expression and epigenetic states showed strong interindividual concordance within a given cell type, almost 10% of the expressed miRNA showed a cell type-specific pattern of expression that was linked to the epigenetic state of their promoter. The tissue-specific miRNA genes were epigenetically repressed in non-expressing cells by DNA methylation (38%) and H3K27me3 (58%), with only a small set of miRNAs (21%) showing a dual epigenetic repression where both DNA methylation and H3K27me3 were present at their promoters, such as MIR10A and MIR10B. Individual miRNA clusters of closely related miRNA gene families can each display cell type-specific repression by the same or complementary epigenetic mechanisms, such as the MIR200 family, and MIR205, where fibroblasts repress MIR200C/141 by DNA methylation, MIR200A/200B/429 by H3K27me3, and MIR205 by both DNA methylation and H3K27me3. Since deregulation of many of the epigenetically regulated miRNAs that we identified have been linked to disease processes such as cancer, it is predicted that compromise of the epigenetic control mechanisms is important for this process. Overall, these results highlight the importance of epigenetic regulation in the control of normal cell type-specific miRNA expression.