PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells.,Modern Pathology

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PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells.
Modern Pathology ( IF 7.1 ) Pub Date : 2020-01-13 , DOI: 10.1038/s41379-020-0457-8
Jakob Hofvander ₁ , Vickie Y Jo ₂ , Christopher D M Fletcher ₂ , Florian Puls ₃ , Uta Flucke ₄ , Jenny Nilsson ₁ , Linda Magnusson ₁ , Fredrik Mertens _{1,

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Affiliation

Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor frequently displaying gene fusions, most of which affect the PHF1 gene. PHF1 encodes plant homeodomain finger protein 1, which is involved in various processes regulating gene transcription, including those orchestrated by the polycomb repressor complex 2. Here, a series of 37 OFMTs, including 18 typical, 9 atypical, and 10 malignant variants, was analyzed with regard to transcriptomic features, gene fusion and copy number status, and/or single-nucleotide variants. The effects on gene expression and chromatin accessibility of three detected fusions (EP400-PHF1, MEAF6-PHF1, and PHF1-TFE3) were further evaluated in fibroblasts. Genomic imbalances showed a progression-related pattern, with more extensive copy number changes among atypical/malignant lesions than among typical OFMTs; loss of the RB1 gene was restricted to atypical/malignant OFMTs, occurring in one-third of the cases. RNA sequencing identified fusion transcripts in >80% of the cases analyzed, including a novel CSMD1-MEAF6. The gene-expression profile of OFMT was distinct from that of other soft tissue tumors, with extensive transcriptional upregulation of genes in OFMT. These findings were largely recapitulated in gene fusion-expressing fibroblast lines, suggesting that genes involved in, e.g., Wnt signaling and/or being regulated through trimethylation of lysine 27 in histone 3 (H3K27me3) are pivotal for OFMT development. The genes showing differentially higher expression in fusion-expressing cells paralleled increased chromatin accessibility, as revealed by ATAC sequencing. Thus, the present study suggests that OFMT develops through gene fusions that have extensive epigenetic consequences.

中文翻译：

PHF1 融合在骨化性纤维粘液样肿瘤和间充质细胞中引起不同的基因表达和染色质可及性特征。

骨化性纤维粘液样肿瘤 (OFMT) 是一种经常显示基因融合的软组织肿瘤，其中大部分影响 PHF1 基因。PHF1 编码植物同源域指蛋白 1，它参与调节基因转录的各种过程，包括由多梳抑制复合物 2 协调的过程。在此，分析了一系列 37 个 OFMT，包括 18 个典型变异、9 个非典型变异和 10 个恶性变异关于转录组学特征、基因融合和拷贝数状态，和/或单核苷酸变异。在成纤维细胞中进一步评估了三种检测到的融合（EP400-PHF1、MEAF6-PHF1 和 PHF1-TFE3）对基因表达和染色质可及性的影响。基因组失衡显示出与进展相关的模式，非典型/恶性病变的拷贝数变化比典型的 OFMT 更广泛；RB1 基因的丢失仅限于非典型/恶性 OFMT，发生在三分之一的病例中。RNA 测序在 >80% 的分析病例中鉴定出融合转录本，包括一种新的 CSMD1-MEAF6。OFMT 的基因表达谱与其他软组织肿瘤不同，OFMT 中基因的转录上调广泛。这些发现在表达基因融合的成纤维细胞系中得到了很大程度的概括，表明参与例如 Wnt 信号传导和/或通过组蛋白 3 (H3K27me3) 中赖氨酸 27 的三甲基化进行调节的基因对于 OFMT 发展至关重要。正如 ATAC 测序所揭示的，在表达融合的细胞中表现出差异更高表达的基因与染色质可及性的增加平行。因此，

更新日期：2020-01-14

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