Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [miR130aKD_Kasumi]. Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML [miR130aKD_Kasumi]

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSC) point to shared core stemness properties. However, discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identified miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impaired lymphoid differentiation and expanded long-term HSC. Integration of protein mass spectrometry and chimeric AGO2 eCLIP-seq identified TBL1XR1 as a primary miR-130a target, whose loss of function phenocopied miR-130a overexpression. Moreover, we found that miR-130a is highly expressed in t(8;21) AML where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells. Overall design: Characterization of gene expression changes following miR-130a knock-down in Kasumi-1 cells. >>>Submitter states: Raw data is being submitted separately to the EGA as we require controlled access for some data.<<<

正常与恶性造血干细胞（hematopoietic stem cells, HSC）的基因表达谱分析与蛋白质组分析结果显示，二者共享核心干性特征。然而mRNA与蛋白质特征之间的不一致性，凸显了微小RNA（microRNAs, miRNAs）介导的转录后调控在调控这一关键关联中的重要作用。本研究鉴定出miR-130a作为造血干细胞自我更新与分化的调控因子。过表达miR-130a会损害淋巴系分化，并扩增长期造血干细胞。通过整合蛋白质质谱与嵌合AGO2增强型交联免疫沉淀测序（enhanced cross-linking immunoprecipitation sequencing, eCLIP-seq）数据，我们鉴定出TBL1XR1是miR-130a的核心靶基因，其功能缺失可模拟miR-130a过表达的表型。此外，我们发现miR-130a在t(8;21)型急性髓系白血病（acute myeloid leukemia, AML）中呈高表达，且其对于维持AML1-ETO介导的致癌分子程序至关重要。本研究证实，在原代细胞中鉴定全面的微小RNA靶标组，可助力发现支撑正常与白血病细胞干性特征的新型基因及分子网络。实验设计：对Kasumi-1细胞中miR-130a敲低后的基因表达变化进行表征分析。>>>提交者说明：由于部分数据需受控访问，原始数据将单独提交至欧洲基因组学档案（European Genome-phenome Archive, EGA）。<<<