Deciphering the genetically interactive network of the DLK1-DIO3 ncRNA locus in the hematopoietic system and in infant leukemias

破译造血系统和婴儿白血病中 DLK1-DIO3 ncRNA 位点的遗传相互作用网络

• 批准号: 510825918
• 负责人: Professor Dr. Jan-Henning Cornelius Klusmann
• 金额: --
• 依托单位: Klinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510825918?language=en
• 关键词: Deciphering; genetically; interactive; network; DLK1

Numerous studies have established the dysregulation of non-coding RNAs (ncRNAs) – in particular of microRNAs (miRNAs) – as a causative factor in leukemogenesis. These studies have largely examined the functions of individual miRNAs or long non-coding RNAs (lncRNAs). However, since 42% of miRNA genes are organized in polycistronic transcripts, studying their interaction is crucial for understanding how miRNAs or miRNA networks control essential cellular functions and cell-fate decisions. In our ncRNA expression atlas of the human hematopoietic system, we uncovered specific and coordinated expression of the DLK1-DIO3 locus – which contains the largest miRNA cluster of the human genome (54 miRNAs; called a miRNA megacluster), numerous box C/D snoRNAs and lncRNAs – in megakaryocytes and megakaryoblastic leukemias. The latter leukemia type occurs most frequently in infants and thus has strong developmental ties. As a part of this ongoing DFG-funded project, we laid a foundation for interrogating the DLK1-DIO3 locus in megakaryopoiesis and acute megakaryoblastic leukemia (AMKL) pathogenesis. We first elucidated an upstream regulatory mechanism in megakaryocytes and megakaryoblasts, allowing us to interfere with expression from the locus. We also identified miRNAs within the locus that drive megakaryocytic differentiation, as well as a novel cis-regulatory long intergenic ncRNA (lincRNA; LINC02285) that affects megakaryopoiesis and controls expression of the locus. Further, we established an LNP packaging and delivery platform in anticipation of the preclinical testing of RNA-centered therapy concepts. In this proposed follow-up project for the Research Unit, we will continue our efforts to dissect the DLK1-DIO3 locus and the ncRNAs within it. We intend to move forward with (1) delineating the network of interactions within the miRNA megacluster – including co-expressed lncRNAs – during normal hematopoiesis and AMKL, (2) resolving the features and mechanisms of individual players, and (3) pre-clinical testing of therapeutic interventions involving these ncRNAs. Overall, this project aims to elucidate how complex organ systems are regulated by interactive genetic networks and how dysregulation of these networks impacts oncogenesis.

许多研究已确定非编码 RNA (ncRNA)（特别是 microRNA (miRNA)）的失调是白血病发生的一个致病因素。这些研究主要检查了单个 miRNA 或长非编码 RNA (lncRNA) 的功能。然而，由于 42% 的 miRNA 基因以多顺反子转录本的形式组织，因此研究它们的相互作用对于理解 miRNA 或 miRNA 网络如何控制重要的细胞功能和在我们的人类造血系统 ncRNA 表达图谱中，我们发现了 DLK1-DIO3 基因座的特异性和协调表达，该基因座包含人类基因组中最大的 miRNA 簇（54 个 miRNA；称为 miRNA 大簇），数量众多。 box C/D snoRNA 和 lncRNA – 在巨核细胞和巨核细胞白血病中，后一种白血病类型最常发生在婴儿中，因此具有很强的作用。作为正在进行的 DFG 资助项目的一部分，我们为探究巨核细胞生成和急性巨核细胞白血病 (AMKL) 发病机制中的 DLK1-DIO3 基因座奠定了基础，使我们能够阐明巨核细胞和巨核细胞的上游调控机制。我们还鉴定了该基因座内驱动巨核细胞分化的 miRNA，以及一种新的 miRNA。顺式调节长基因间 ncRNA（lincRNA；LINC02285）影响巨核细胞生成并控制基因座的表达。此外，我们建立了一个 LNP 包装和递送平台，以期对以 RNA 为中心的治疗概念进行临床前测试。对于研究单位的项目，我们将继续努力剖析 DLK1-DIO3 基因座及其中的 ncRNA，我们打算推进 (1)。描绘正常造血和 AMKL 期间 miRNA 巨簇（包括共表达的 lncRNA）内的相互作用网络，（2）解析个体参与者的特征和机制，以及（3）涉及这些 ncRNA 的治疗干预的临床前测试。 ，该项目旨在阐明复杂的器官系统如何通过交互式遗传网络进行调节，以及这些网络的失调如何影响肿瘤发生。