Krushkal Julia, Jensen Travis L, Wright George, Zhao Yingdong
Division of Cancer Treatment and Diagnosis, Biometric Research Program, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA.
The Emmes Company, LLC, Rockville, MD, 20850, USA.
Clin Epigenetics. 2025 May 25;17(1):83. doi: 10.1186/s13148-025-01883-3.
Imprinted genes are epigenetically regulated in normal tissues to follow monoallelic expression according to the parent of origin of each allele. Some of these patterns are dysregulated in cancer.
We developed a novel computational multi-omic pipeline to evaluate monoallelic and biallelic expression patterns based on matched RNA-seq expression data, whole-exome sequencing information, and copy number data. We analyzed allelic expression of the entire genes, individual isoforms, and each exon of 59,283 autosomal protein-coding and ncRNA genes, with a focus on 94 genes previously reported to be imprinted. We analyzed 108 cell lines from 9 different tumor histologies using molecular data from the DepMap Portal for the Cancer Cell Line Encyclopedia. Allelic expression patterns of imprinted genes and isoforms in tumor cells were variable. We also identified additional genes and isoforms with predominantly monoallelic expression due to a variety of potential mechanisms. We provide a novel public dataset of transcriptome-wide allelic expression patterns in cell lines from diverse tumor categories, which can serve as a resource for future cancer studies. We examined associations of in vitro cell line response to antitumor agents and repurposed drugs with allelic patterns and overall levels of isoform expression of imprinted genes and of additional genes with predominantly monoallelic expression. Drug response was associated with isoform expression patterns of multiple imprinted genes including CPA4, DGCR6, DNMT1, GNAS, GRB10, H19, NAA60, OSBPL5, PHACTR2, and ZFAT, predominantly monoallelically expressed MAP2K5 and BCLAF1, and additional predominantly monoallelically expressed genes. Multiple associations may be related to mechanisms of drug activity, including associations between the response to the DNA damaging agents and allelic expression of ZFAT, CDC27, and BCLAF1 isoforms, and the response to inhibitors of multiple signaling pathways with expression patterns of GNAS isoforms.
Tumor cells have a range of monoallelic and biallelic expression patterns in both imprinted and non-imprinted genes and are likely affected by the complex interplay among changes in allelic expression, sequence variants, copy number changes, and expression changes of biologically important genes. Multiple isoform-specific patterns of allelic expression were associated with drug response, indicating complex mechanisms of cancer chemoresistance.
印记基因在正常组织中通过表观遗传调控，根据每个等位基因的亲本来源遵循单等位基因表达。其中一些模式在癌症中失调。
我们开发了一种新颖的计算多组学流程，以基于匹配的RNA测序表达数据、全外显子测序信息和拷贝数数据评估单等位基因和双等位基因表达模式。我们分析了59283个常染色体蛋白质编码和非编码RNA基因的全部基因、单个异构体和每个外显子的等位基因表达，重点关注先前报道的94个印记基因。我们使用来自癌症细胞系百科全书DepMap门户的分子数据，分析了来自9种不同肿瘤组织学的108个细胞系。肿瘤细胞中印记基因和异构体的等位基因表达模式各不相同。我们还鉴定出由于多种潜在机制而主要呈现单等位基因表达的其他基因和异构体。我们提供了一个来自不同肿瘤类别的细胞系中转录组范围等位基因表达模式的新颖公共数据集，可作为未来癌症研究的资源。我们研究了体外细胞系对抗肿瘤药物和重新利用药物的反应与印记基因以及主要呈现单等位基因表达的其他基因的等位基因模式和异构体表达总体水平之间的关联。药物反应与多个印记基因的异构体表达模式相关，包括CPA4、DGCR6、DNMT1、GNAS、GRB10、H19、NAA60、OSBPL5、PHACTR2和ZFAT，主要呈现单等位基因表达的MAP2K5和BCLAF1，以及其他主要呈现单等位基因表达的基因。多种关联可能与药物活性机制有关，包括对DNA损伤剂的反应与ZFAT、CDC27和BCLAF1异构体的等位基因表达之间的关联，以及对多种信号通路抑制剂的反应与GNAS异构体的表达模式之间的关联。
肿瘤细胞在印记基因和非印记基因中都有一系列单等位基因和双等位基因表达模式，并且可能受到等位基因表达变化、序列变异、拷贝数变化以及生物学重要基因表达变化之间复杂相互作用的影响。多种异构体特异性的等位基因表达模式与药物反应相关，表明癌症化疗耐药的复杂机制。
