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首页> 外文期刊>BMC Medical Genomics >Transposase mapping identifies the genomic targets of BAP1 in uveal melanoma
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Transposase mapping identifies the genomic targets of BAP1 in uveal melanoma

机译：转座酶定位鉴定葡萄膜黑色素瘤中BAP1的基因组靶标

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BAP1 is a histone deubiquitinase that acts as a tumor and metastasis suppressor associated with disease progression in human cancer. We have used the “Calling Card System” of transposase-directed transposon insertion mapping to identify the genomic targets of BAP1 in uveal melanoma (UM). This system was developed to identify the genomic loci visited by transcription factors that bind directly to DNA; our study is the first use of the system with a chromatin-remodeling factor that binds to histones but does not interact directly with DNA. The transposase piggyBac (PBase) was fused to BAP1 and expressed in OCM-1A UM cells. The insertion of transposons near BAP1 binding sites in UM cells were identified by genomic sequencing. We also examined RNA expression in the same OCM-1A UM cells after BAP1 depletion to identify BAP1 binding sites associated with BAP1-responsive genes. Sets of significant genes were analyzed for common pathways, transcription factor binding sites, and ability to identify molecular tumor classes. We found a strong correlation between multiple calling-card transposon insertions targeted by BAP1-PBase and BAP1-responsive expression of adjacent genes. BAP1-bound genomic loci showed narrow distributions of insertions and were near transcription start sites, consistent with recruitment of BAP1 to these sites by specific DNA-binding proteins. Sequence consensus analysis of BAP1-bound sites showed enrichment of motifs specific for YY1, NRF1 and Ets transcription factors, which have been shown to interact with BAP1 in other cell types. Further, a subset of the BAP1 genomic target genes was able to discriminate aggressive tumors in published gene expression data from primary UM tumors. The calling card methodology works equally well for chromatin regulatory factors that do not interact directly with DNA as for transcription factors. This technique has generated a new and expanded list of BAP1 targets in UM that provides important insight into metastasis pathways and identifies novel potential therapeutic targets.
机译：BAP1是一种组蛋白去泛素酶，可作为与人类癌症疾病进展相关的肿瘤和转移抑制因子。我们已使用转座酶定向转座子插入作图的“电话卡系统”来鉴定葡萄膜黑色素瘤（UM）中BAP1的基因组靶标。开发该系统以鉴定直接与DNA结合的转录因子访问的基因组位点;我们的研究是该系统首次使用具有与组蛋白结合但不直接与DNA相互作用的染色质重塑因子的系统。转座子piggyBac（PBase）与BAP1融合并在OCM-1A UM细胞中表达。通过基因组测序鉴定了UM细胞中BAP1结合位点附近的转座子的插入。我们还检查了BAP1耗尽后在同一OCM-1A UM细胞中的RNA表达，以确定与BAP1反应基因相关的BAP1结合位点。分析了重要基因集的常见途径，转录因子结合位点以及鉴定分子肿瘤类别的能力。我们发现BAP1-PBase靶向的多个电话卡转座子插入与邻近基因的BAP1反应性表达之间有很强的相关性。 BAP1绑定的基因组位点显示插入的分布狭窄，并且靠近转录起始位点，与BAP1通过特定的DNA结合蛋白募集到这些位点一致。对BAP1结合位点的序列共有分析表明，YY1，NRF1和Ets转录因子具有特定的基序，这些基序已在其他细胞类型中与BAP1相互作用。此外，BAP1基因组靶基因的一个子集能够从原发性UM肿瘤中区分已发表的基因表达数据中的侵袭性肿瘤。电话卡方法对于不直接与DNA相互作用的染色质调节因子和转录因子都同样有效。这项技术已在UM中生成了新的BAP1靶标，并对其进行了扩展，从而提供了对转移途径的重要见解，并确定了新的潜在治疗靶标。

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