Diacofotaki Anna, Loriot Axelle, De Smet Charles
Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Group of Computational Biology and Bioinformatics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Cancers (Basel). 2022 Feb 16;14(4):1007. doi: 10.3390/cancers14041007.
Genome-wide loss of DNA methylation is commonly observed in human cancers, but its impact on the tumor transcriptome remains ill-defined. Previous studies demonstrated that this epigenetic alteration causes aberrant activation of a germline-specific gene expression program. Here, we examined if DNA hypomethylation in tumors also leads to de-repression of gene clusters with other tissue specificities. To this end, we explored transcriptomic and methylomic datasets from human lung adenocarcinoma (LUAD) cell lines, normal lung, and lung alveolar type II cells, considered as the origin of LUAD. Interestingly, DNA demethylation in LUAD cell lines was associated with activation of not only germline-specific (CG) genes, but also gene clusters displaying specific expression in the gastrointestinal tract (GI), or in stratified epithelia (SE). Consistently, genes from all three clusters showed highly specific patterns of promoter methylation among normal tissues and cell types, and were generally sensitive to induction by a DNA demethylating agent. Analysis of TCGA datasets confirmed that demethylation and activation of CG, GI and SE genes also occurs in vivo in LUAD tumor tissues, in association with global genome hypomethylation. For genes of the GI cluster, we demonstrated that HNF4A is a necessary factor for transcriptional activation following promoter demethylation. Interestingly, expression of several SE genes, in particular , correlated with both tumor grade and reduced patient survival. Together, our study uncovers novel cell-type specific gene clusters that become aberrantly activated in LUAD tumors in association with genome-wide hypomethylation.
全基因组DNA甲基化缺失在人类癌症中普遍存在，但其对肿瘤转录组的影响仍不明确。先前的研究表明，这种表观遗传改变会导致种系特异性基因表达程序的异常激活。在此，我们研究了肿瘤中的DNA低甲基化是否也会导致具有其他组织特异性的基因簇去抑制。为此，我们探索了来自人肺腺癌（LUAD）细胞系、正常肺组织和被认为是LUAD起源的肺II型肺泡细胞的转录组和甲基化组数据集。有趣的是，LUAD细胞系中的DNA去甲基化不仅与种系特异性（CG）基因的激活有关，还与在胃肠道（GI）或复层上皮（SE）中显示特异性表达的基因簇有关。一致地，来自所有三个簇的基因在正常组织和细胞类型中显示出高度特异性的启动子甲基化模式，并且通常对DNA去甲基化剂的诱导敏感。对TCGA数据集的分析证实，CG、GI和SE基因的去甲基化和激活在LUAD肿瘤组织的体内也会发生，与全基因组低甲基化相关。对于GI簇的基因，我们证明HNF4A是启动子去甲基化后转录激活的必要因子。有趣的是，几个SE基因的表达，特别是 ，与肿瘤分级和患者生存率降低相关。总之，我们的研究发现了与全基因组低甲基化相关的在LUAD肿瘤中异常激活的新型细胞类型特异性基因簇。
