Institute of Human Genetics, Polish Academy of Sciences Poznan, Poznan, Poland.
Interdisciplinary Center for Bioinformatics, Transcriptome Bioinformatics, University of Leipzig, Leipzig, Germany.
PLoS One. 2023 Mar 24;18(3):e0283186. doi: 10.1371/journal.pone.0283186. eCollection 2023.
MicroRNAs (miRNAs) are small non coding RNAs responsible for posttranscriptional regulation of gene expression. Even though almost 2000 precursors have been described so far, additional miRNAs are still being discovered in normal as well as malignant cells. Alike protein coding genes, miRNAs may acquire oncogenic properties in consequence of altered expression or presence of gain or loss of function mutations. In this study we mined datasets from miRNA expression profiling (miRNA-seq) of 7 classic Hodgkin Lymphoma (cHL) cell lines, 10 non-Hodgkin lymphoma (NHL) cell lines and 56 samples of germinal center derived B-cell lymphomas. Our aim was to discover potential novel cHL oncomiRs not reported in miRBase (release 22.1) and expressed in cHL cell lines but no other B-cell lymphomas. We identified six such miRNA candidates in cHL cell lines and verified the expression of two of them encoded at chr2:212678788-212678849 and chr5:168090507-168090561 (GRCh38). Interestingly, we showed that one of the validated miRNAs (located in an intron of the TENM2 gene) is expressed together with its host gene. TENM2 is characterized by hypomethylation and open chromatin around its TSS in cHL cell lines in contrast to NHL cell lines and germinal centre B-cells respectively. It indicates an epigenetic mechanism responsible for aberrant expression of both, the TENM2 gene and the novel miRNA in cHL cell lines. Despite the GO analysis performed with the input of the in silico predicted novel miRNA target genes did not reveal ontologies typically associated with cHL pathogenesis, it pointed to several interesting candidates involved in i.e. lymphopoiesis. These include the lymphoma related BCL11A gene, the IKZF2 gene involved in lymphocyte development or the transcription initiator GTF2H1.
微小 RNA(miRNA)是负责基因表达转录后调控的小型非编码 RNA。尽管迄今为止已经描述了近 2000 个前体,但在正常和恶性细胞中仍在发现额外的 miRNA。与编码蛋白的基因一样,miRNA 可能由于表达改变或获得功能获得或丧失突变而获得致癌特性。在这项研究中,我们挖掘了 7 个经典霍奇金淋巴瘤(cHL)细胞系、10 个非霍奇金淋巴瘤(NHL)细胞系和 56 个生发中心衍生 B 细胞淋巴瘤样本的 miRNA 表达谱(miRNA-seq)数据集。我们的目的是发现潜在的新的 cHL 致癌 miRNA,这些 miRNA 在 miRBase(版本 22.1)中没有报道,并且在 cHL 细胞系中表达,但在其他 B 细胞淋巴瘤中不表达。我们在 cHL 细胞系中鉴定了六个这样的 miRNA 候选物,并验证了其中两个在 chr2:212678788-212678849 和 chr5:168090507-168090561(GRCh38)上的表达。有趣的是,我们表明,验证的 miRNA 之一(位于 TENM2 基因的内含子中)与其宿主基因一起表达。与 NHL 细胞系和生发中心 B 细胞相比,TENM2 基因在 cHL 细胞系中表现为低甲基化和开放染色质。这表明一种表观遗传机制负责异常表达 TENM2 基因和新型 miRNA 在 cHL 细胞系中。尽管对输入的 GO 分析进行了分析,但与 cHL 发病机制相关的生物学过程并没有预测到新型 miRNA 靶基因通常相关的本体论,它指向了几个有趣的候选基因,这些候选基因涉及淋巴发生,包括淋巴瘤相关的 BCL11A 基因、参与淋巴细胞发育的 IKZF2 基因或转录起始因子 GTF2H1。
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