Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.
Genome Res. 2011 Dec;21(12):2026-37. doi: 10.1101/gr.123935.111. Epub 2011 Aug 26.
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 nonexpressing 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.
表观遗传机制是细胞类型特异性基因（包括 miRNA）的重要调节因子。为了鉴定受表观遗传机制调控的细胞类型特异性 miRNA，我们对三对同源的人乳腺上皮细胞（HMEC）和人乳腺成纤维细胞（HMF）中的 miRNA 表达和表观遗传状态进行了全面分析，这两种细胞类型代表了特定器官中通常存在的两种分化细胞类型，每种细胞类型都具有独特的表型和独特的表观遗传型。虽然在给定的细胞类型中，miRNA 表达和表观遗传状态在个体间具有很强的一致性，但几乎有 10%的表达 miRNA 表现出与启动子表观遗传状态相关的细胞类型特异性表达模式。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，只有一小部分 miRNA（21%）表现出双重表观遗传抑制，即在其启动子处同时存在 DNA 甲基化和 H3K27me3，如 MIR10A 和 MIR10B。密切相关的 miRNA 基因家族的单个 miRNA 簇可以通过相同或互补的表观遗传机制表现出细胞类型特异性抑制，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。由于我们鉴定的许多受表观遗传调控的 miRNA 的失调与癌症等疾病过程有关，因此可以预测，表观遗传控制机制的破坏对该过程很重要。总的来说，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 表达中的重要性。
