Pcid2调控造血干细胞向淋巴祖细胞谱系建立的分子机制研究

血液细胞谱系建立机制的研究是医学领域的前瞻课题，揭示造血干细胞（HSC）的发育分化和淋巴细胞谱系建立的命运决定机制，将为血液病发病机制提供理论依据。血液细胞谱系建立的命运决定依赖HSC干性相关基因的关闭和谱系相关特异基因的表达，此过程受到表观遗传的精细调节，染色质重塑因子、转录因子等均在此过程中发挥重要作用。申请人的前期工作发现，Pcid2在造血系的基因敲除促进小鼠骨髓HSC向淋巴祖细胞发育，Pcid2通过与重塑复合物SRCAP的组分ZNHIT1相互作用，调控了SRCAP复合物重塑活性及谱系重要基因表达。我们将深入探讨在HSC向淋巴祖细胞谱系建立过程中Pcid2对谱系命运决定的调节作用，探究Pcid2通过调控SRCAP重塑复合物促进转录因子PU.1的激活及下游靶基因开放表达的表观遗传调控机制，探明其与人类造血系统疾病发病的关系。

Study on mechanisms of hematopoietic lineage commitment is a subject in the frontiers of medical field. Discovering the fate decision mechanisms of HSC development and differentiation, and lymphoid lineage commitment will provide theoretical basis on blood disease pathogenesis. Fate decision of hematopoietic lineage commitment is dependent on stemness-related genes closing and lineage commitment-related specific genes opening, which are finely controlled by epigenetic regulation. Chromatin remodelers and transcription factors play pivital roles in this process. Our preliminary data show that Pcid2 deletion in hematopoietic system promotes mouse bone marrow hematopoietic stem cells differentiating into lymphoid progenitors. Pcid2 regulates the chromatin remodeling activity of SRCAP and key gene expression in lymphoid progenitor lineage commitment by its association with ZNHIT1, the component of SRCAP complex. This study is to further discuss the regulatory effect of Pcid2 for the fate decision in the process of HSC committing to lymphoid progenitor lineage, to explore epigenetic regulation mechanisms of Pcid2 in promoting transcription factor PU.1 activation and downstream target gene expression through SRCAP remodeling activity, and to verify the relationship between Pcid2 with the pathogenesis of human blood diseases.