长链非编码RNA在造血髓系链系呈递及分化发育中的功能及机制研究

Myeloid development is a highly orchestrated process that generating distinct lineage-committed blood cells from a single multipotent hematopoietic stem cell. However, the detailed mechanism has not been uncovered completely. Long non-coding RNA (lncRNA) are a group of molecules that function in gene regulation by interacting with chromatin remodeling and modifying enzymes, RNA binding proteins and other small RNAs. LncRNA participates in a wide-repertoire of biological processes, and multiple lines of evidence increasingly link mutations and dysregulations of lncRNAs to diverse human diseases. Our previous study has revealed the stage-specific expression and function of certain lncRNA, indicating their essential roles during myeloid development. In this study, we focus on the " regulation of hematopoietic development and related diseases", aiming at the unresolved questions in the field of hematopoiesis: how lncRNA interact with other regulators to orchestrate such a complex process, and how this regulation involved in leukemogenesis? We will further identify the expression of lncRNA and its interaction complex systematically during myeloid lineage commitment and AML development. Furthermore, we will investigate the molecular mechanism of lncRNA regulation, and examine their roles in controlling myeloid lineage commitment and AML treatment in vivo and in vitro. These results will create a new vision for clarifying the mechanism of myeloid lineage commitment and establish the theoretical basis for developing new method for AML diagnose and therapy.

造血髓系发育是一个复杂而精密的调控过程，链系呈递是其间细胞命运选择的关键环节,但其分子基础尚未完全揭示。长非编码RNA（lncRNA）是近来发现的一类可调控多个重要生命过程的大分子。我们前期研究发现lncRNA在髓系链系呈递及后续发育中呈显著的阶段特异性表达，并初步揭示了部分lncRNA的作用机制，提示lncRNA在这一过程中的重要作用。本项目针对指南方向“造血系统发育调控及相关疾病发生”，拟围绕“lncRNA及其互作复合体如何调控髓系链系呈递及分化发育、其功能异常如何导致髓系白血病”这一关键科学问题展开研究：系统分析lncRNA及其互作复合体在髓系发育中的动态表达特征；重点研究关键组分在髓系发育中的功能及调控机制；深入探讨lncRNA及其互作复合体的表达紊乱及遗传异常导致髓系白血病的机制。这些将为阐明造血髓系链系呈递及分化发育的分子机理开辟新视野，并为髓系白血病的诊断和治疗奠定理论基础。

造血髓系发育是一个复杂而精密的调控过程，谱系分化是其间细胞命运选择的关键环节,但其分子基础尚未完全揭示。长非编码RNA（lncRNA）是近来发现的一类可调控多个重要生命过程的大分子。本项目通过多组学测序和分析揭示了造血干细胞发育及髓系谱系分化过程中LncRNA动态变化和调控网络；明确了多个关键LncRNA-复合体（如H19, HBBP1, BGLT3, molnc-301b等）在髓系发育中的功能机理，发现了假基因来源LncRNA以及microRNA初级转录本来源LncRNA调控髓系发育的新机制；揭示了HBBP1和BGLT3在血液系统疾病中的潜在应用价值，并发表11篇有较高影响力的研究论文。为阐明造血髓系谱系分化发育的分子机理开辟了新视野，并为髓系白血病的诊断和治疗奠定理论了基础。