Bioengineering and Bioinformatics Program, Department of Pathology, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX, 77030, USA.
BMC Med Genomics. 2011 Feb 23;4:19. doi: 10.1186/1755-8794-4-19.
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.
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.
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.
The presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis.
骨髓增生异常综合征（MDS）是一种具有全球发病率不断上升的前白血病性疾病，但治疗选择非常有限。关于小调控 RNA 及其如何导致 MDS 的发病机制、进展和转录组变化，人们知之甚少。
使用下一代测序对患者的原始骨髓细胞进行短 RNA（RNA-seq）筛选。使用相同细胞的外显子芯片进行基因表达谱分析，并获得了 98 例患者的其他测量值。提出了综合生物信息学算法，并进行了途径和本体分析。
在低级别 MDS 中，观察结果表明通过 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。与 MDS 相关和新型 miRNA 的表达差异较大，包括与 miRNA 星（miRNA*）基序匹配的 48 个序列。检测到的物种被预测可调节疾病阶段特异性分子功能和途径，包括细胞凋亡和对 DNA 损伤的反应。在高级别 MDS 中，结果表明通过转移 RNA（tRNA）进行广泛的翻译后编辑，为该疾病阶段的细胞凋亡减少提供了潜在联系。生物信息学分析证实了与 MDS 相关的 miRNA 和 TFs 的重要调节作用，并增强了 miRNA*的生物学意义。“RNA 聚合酶 II 启动子”被确定为受控制最严格的生物学功能。我们建议它们受 miRNA 主导的反馈环控制，这可能与低级别和高级别 MDS 之间观察到的明显不同的 miRNA 数量有关。
所呈现的结果提供了新的发现，为进一步研究诊断生物标志物、靶向治疗和 MDS 发病机制奠定了基础。
