Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
BMC Genomics. 2023 Jul 27;24(1):425. doi: 10.1186/s12864-023-09526-8.
Growing evidence indicates that RNA methylation plays a fundamental role in epigenetic regulation, which is associated with the tumorigenesis and drug resistance. Among them, acute myeloid leukemia (AML), as the top acute leukemia for adults, is a deadly disease threatening human health. Although N7-methylguanosine (m7G) has been identified as an important regulatory modification, its distribution has still remained elusive.
The present study aimed to explore the long non-coding RNA (lncRNA) functional profile of m7G in AML and drug-resistant AML cells. The transcriptome-wide m7G methylation of lncRNA was analyzed in AML and drug-resistant AML cells. RNA MeRIP-seq was performed to identify m7G peaks on lncRNA and differences in m7G distribution between AML and drug-resistant AML cells. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to predict the possible roles and m7G-associated pathway.
Using m7G peak sequencing, it was found that a sequence motif was necessary for m7G methylation in drug-resistant AML lncRNA. Unsupervised hierarchical cluster analysis confirmed that lncRNA m7G methylation occurred more frequently in drug-resistant AML cells than in AML cells. RNA sequencing demonstrated that more genes were upregulated by methylation in drug-resistant AML cells, while methylation downregulated more genes in AML cells. The GO and KEGG pathway enrichment analyses revealed that genes having a significant correlation with m7G sites in lncRNA were involved in drug-resistant AML signaling pathways.
Significant differences in the levels and patterns of m7G methylation between drug-resistant AML cells and AML cells were revealed. Furthermore, the cellular functions potentially influenced by m7G in drug-resistant AML cells were predicted, providing evidence implicating m7G-mediated lncRNA epigenetic regulation in the progression of drug resistance in AML. These findings highlight the involvement of m7G in the development of drug resistance in AML.
越来越多的证据表明，RNA 甲基化在表观遗传调控中起着基本作用，而表观遗传调控与肿瘤发生和耐药性有关。其中，急性髓细胞白血病（AML）作为成人中最常见的急性白血病，是一种威胁人类健康的致命疾病。尽管 N7-甲基鸟苷（m7G）已被确定为一种重要的调控修饰，但它的分布仍然难以捉摸。
本研究旨在探索 AML 和耐药性 AML 细胞中 m7G 对长非编码 RNA（lncRNA）功能的影响。对 AML 和耐药性 AML 细胞中的 lncRNA 的转录组范围的 m7G 甲基化进行了分析。进行 RNA MeRIP-seq 以鉴定 lncRNA 上的 m7G 峰，并比较 AML 和耐药性 AML 细胞之间 m7G 分布的差异。进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路富集分析，以预测可能的作用和与 m7G 相关的通路。
通过 m7G 峰测序发现，耐药性 AML lncRNA 中 m7G 甲基化需要一个序列基序。无监督层次聚类分析证实，耐药性 AML 细胞中 lncRNA m7G 甲基化比 AML 细胞更频繁。RNA 测序表明，耐药性 AML 细胞中，更多的基因因甲基化而上调，而 AML 细胞中则有更多的基因因甲基化而下调。GO 和 KEGG 通路富集分析表明，lncRNA 中与 m7G 位点有显著相关性的基因参与了耐药性 AML 信号通路。
揭示了耐药性 AML 细胞与 AML 细胞之间 m7G 甲基化水平和模式的显著差异。此外，预测了可能受 m7G 影响的耐药性 AML 细胞中的细胞功能，为 m7G 介导的 lncRNA 表观遗传调控在 AML 耐药进展中的作用提供了证据。这些发现强调了 m7G 在 AML 耐药发展中的作用。
