Deciphering the genetic 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: 354644272
• 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 Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/354644272?language=en
• 关键词: Deciphering; genetic; interactive; network; DLK1

Numerous studies have recently established the dysregulated expression of non-coding RNAs (ncRNAs), in particular of microRNAs (miRNAs), as a causative factor in leukemogen-esis. These studies have largely examined the function of individual miRNAs or long non-coding RNAs (lncRNAs). However, our previous work on the miR-99/100~125b clusters demonstrated the importance of the genomic context for the function of non-coding genes. We showed that polycistronically organized ncRNAs can have both synergistic and comple-mentary functions, reinforcing and controlling each other. Since 42% of the miRNA genes are organized in polycistronic transcripts, their interaction in controlling essential cellular functions and cell-fate decisions has to be understood. This is essential to obey the consequences of therapeutic miRNA-interference in oncology, hematology or regenerative medicine. To gain specific and general insights into the structure, regulation and function of ncRNA/ mRNA clusters in the human blood system, we will dissect in this project (accompanying the Heisenberg Programme), the DLK1-DIO3 locus during megakaryopoiesis and the pathogen-esis of acute megakaryoblastic leukemias. The DLK1-DIO3 locus contains the largest miRNA cluster of the human genome (54 miRNAs; called miRNA-mega cluster), numerous box C / D snoRNAs and lncRNAs expressed from the maternal allele. Integrative analyses of our onto-genetic human ncRNA expression atlas of the hematopoietic system have uncovered a spe-cific expression of this locus in megakaryocytes. This expression pattern is also found in megakaryoblastic leukemias that frequently occur in infants. Thus, the overall aim of this project is to elucidate how complex organ systems are regu-lated by interactive genetic networks and how dysregulation of these networks impacts on-cogenesis. These insights now become reachable by recent advances in the genome editing and genome-wide transcriptional regulation. In addition, novel humanized mouse models for patient-derived xenografts will allow efficient preclinical testing of innovative treatment con-cepts for infant leukemias, and therefore the rapid transition to the clinics.

最近许多研究已证实非编码 RNA (ncRNA)，特别是 microRNA (miRNA) 的表达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 或长链非编码 RNA (lncRNA) 的功能。然而，我们之前对 miR-99/100~125b 簇的研究证明了基因组背景对于非编码基因功能的重要性。我们表明，多顺反子组织的 ncRNA 可以具有协同和互补的功能，相互增强和控制。由于 42% 的 miRNA 基因以多顺反子转录本的形式组织，因此必须了解它们在控制基本细胞功能和细胞命运决定方面的相互作用。这对于遵守肿瘤学、血液学或再生医学中治疗性 miRNA 干扰的后果至关重要。为了获得对人类血液系统中 ncRNA/ mRNA 簇的结构、调控和功能的具体和一般性的了解，我们将在这个项目（伴随海森堡计划）中剖析巨核细胞生成过程中的 DLK1-DIO3 基因座以及急性巨核细胞白血病。 DLK1-DIO3 基因座包含人类基因组中最大的 miRNA 簇（54 个 miRNA；称为 miRNA-mega 簇）、大量由母体等位基因表达的 box C/D snoRNA 和 lncRNA。对我们的造血系统个体遗传人类 ncRNA 表达图谱的综合分析发现了该基因座在巨核细胞中的特异性表达。这种表达模式也存在于婴儿中常见的巨核细胞白血病中。因此，该项目的总体目标是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同生。现在，通过基因组编辑和全基因组转录调控的最新进展，这些见解变得可以实现。此外，用于患者异种移植的新型人源化小鼠模型将允许对婴儿白血病创新治疗概念进行有效的临床前测试，从而快速过渡到临床。