Metastasis-associated protein ribosomal RNA processing 1 homolog B (RRP1B) modulates metastasis through regulation of histone methylation.
Metastasis-associated protein ribosomal RNA processing 1 homolog B (RRP1B) modulates metastasis through regulation of histone methylation.
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DOI：
10.1158/1541-7786.mcr-14-0167
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发表时间：
2014-12
期刊：
影响因子：
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通讯作者：
Crawford NP
中科院分区：
文献类型：
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作者：
Lee M;Dworkin AM;Lichtenberg J;Patel SJ;Trivedi NS;Gildea D;Bodine DM;Crawford NP
核糖体RNA加工1同源物B（RRP 1 B）的过表达诱导了准确预测乳腺癌患者预后的转录谱。然而，RRP 1B调节转录的机制尚不清楚。在这里，RRP 1B的染色质结合特性进行了检查，以确定它如何调节转移相关的转录。为了鉴定全基因组RRP 1B结合位点，使用针对内源性RRP 1B的抗体在人乳腺癌细胞系MDA-MB-231和HeLa细胞中进行高通量ChIP-seq。还通过ChIP-seq检查了抑制标记如组蛋白H3赖氨酸9三甲基化（H3 K9 me 3）的全局变化。对这些样品的分析在MDA-MB-231细胞中鉴定了339个结合区域，在HeLa细胞中鉴定了689个RRP 1B结合区域。其中，136个区域是两种细胞系共有的。这些RRP 1B结合区域的基因表达分析显示，转录抑制是RRP 1B结合染色质的主要结果。ChIP-reChIP分析表明，RRP 1B与异染色质相关蛋白TRIM 28/KAP 1和异染色质蛋白1-α CBX 5/HP 1 α共占据基因表达降低的位点。这些位点的RRP 1B占有率也与较高的H3 K9 me 3水平相关，表明TRIM 28/HP 1 α复合物介导的异染色质化。此外，与转移抑制相关的RRP 1B上调诱导了组蛋白甲基化的整体变化。RRP 1B是一种乳腺癌转移抑制因子，通过异染色质化和转录抑制调节基因表达，这有助于我们理解人类乳腺癌中驱动预后基因表达的机制。
Over-expression of Ribosomal RNA Processing 1 Homolog B (RRP1B) induces a transcriptional profile that accurately predicts patient outcome in breast cancer. However, the mechanism by which RRP1B modulates transcription is unclear. Here, the chromatin-binding properties of RRP1B were examined to define how it regulates metastasis-associated transcription. To identify genome-wide RRP1B binding sites, high-throughput ChIP-seq was performed in the human breast cancer cell line MDA-MB-231 and HeLa cells using antibodies against endogenous RRP1B. Global changes in repressive marks such as histone H3 lysine 9 trimethylation (H3K9me3) were also examined by ChIP-seq. Analysis of these samples identified 339 binding regions in MDA-MB-231 cells and 689 RRP1B binding regions in HeLa cells. Among these, 136 regions were common to both cell lines. Gene expression analyses of these RRP1B-binding regions revealed that transcriptional repression is the primary result of RRP1B binding to chromatin. ChIP-reChIP assays demonstrated that RRP1B co-occupies loci with decreased gene expression with the heterochromatin-associated proteins, tripartite motif-containing protein 28 (TRIM28/KAP1) and heterochromatin protein 1-α (CBX5/HP1α). RRP1B occupancy at these loci was also associated with higher H3K9me3 levels, indicative of heterochromatinization mediated by the TRIM28/HP1α complex. In addition, RRP1B up-regulation, which is associated with metastasis suppression, induced global changes in histone methylation. RRP1B, a breast cancer metastasis suppressor, regulates gene expression through heterochromatinization and transcriptional repression, which helps our understanding of mechanisms that drive prognostic gene expression in human breast cancer.