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首页> 外文期刊>BMC Medical Genomics >Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes
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Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes

机译：小型非编码RNA的下一代测序和骨髓增生异常综合征的转录调控的综合分析

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Background Myelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options. Little is known about small regulatory RNAs and how they contribute to pathogenesis, progression and transcriptome changes in MDS. Methods Patients' primary marrow cells were screened for short RNAs (RNA-seq) using next generation sequencing. Exon arrays from the same cells were used to profile gene expression and additional measures on 98 patients obtained. Integrative bioinformatics algorithms were proposed, and pathway and ontology analysis performed. Results In low-grade MDS, observations implied extensive post-transcriptional regulation via microRNAs (miRNA) and the recently discovered Piwi interacting RNAs (piRNA). Large expression differences were found for MDS-associated and novel miRNAs, including 48 sequences matching to miRNA star (miRNA*) motifs. The detected species were predicted to regulate disease stage specific molecular functions and pathways, including apoptosis and response to DNA damage. In high-grade MDS, results suggested extensive post-translation editing via transfer RNAs (tRNAs), providing a potential link for reduced apoptosis, a hallmark for this disease stage. Bioinformatics analysis confirmed important regulatory roles for MDS linked miRNAs and TFs, and strengthened the biological significance of miRNA*. The "RNA polymerase II promoters" were identified as the tightest controlled biological function. We suggest their control by a miRNA dominated feedback loop, which might be linked to the dramatically different miRNA amounts seen between low and high-grade MDS. Discussion The presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis.
机译：背景骨髓增生异常综合症（MDSS）是白血病前疾病，全世界范围内的发病率均在上升，但治疗选择却非常有限。人们对小调节RNA及其如何促进MDS的发病机理，进展和转录组变化了解甚少。方法使用下一代测序技术筛选患者的原代骨髓细胞的短RNA（RNA-seq）。来自相同细胞的外显子阵列用于分析基因表达，并对98名患者进行了其他检测。提出了集成生物信息学算法，并进行了路径和本体分析。结果在低级MDS中，观察表明通过microRNA（miRNA）和最近发现的Piwi相互作用RNA（piRNA）进行广泛的转录后调控。发现与MDS相关的新型miRNA的表达差异很大，包括与miRNA star（miRNA *）模体匹配的48个序列。预计检测到的物种将调节疾病阶段特定的分子功能和途径，包括细胞凋亡和对DNA损伤的反应。在高级MDS中，结果表明可通过转移RNA（tRNA）进行广泛的翻译后编辑，为减少凋亡提供了可能的联系，而凋亡是这一疾病阶段的标志。生物信息学分析证实了MDS连接的miRNA和TF的重要调控作用，并增强了miRNA *的生物学意义。 “ RNA聚合酶II启动子”被鉴定为最严格的受控生物学功能。我们建议通过miRNA为主的反馈环控制它们，这可能与在低级和高级MDS之间看到的miRNA量显着不同有关。讨论提出的结果提供了新颖的发现，为进一步研究诊断性生物标志物，靶向疗法和MDS发病机理研究奠定了基础。

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