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

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.

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。

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，将为血液病研究及细胞免疫治疗提供理论依据。本项目证明了Pcid2分子在骨髓造血多能干祖细胞(MPP)高表达。Pcid2在造血系中的特异性基因敲除促进外周淋巴细胞增多，导致骨髓造血干祖细胞LSK及MPP群数量减少，共同淋巴系祖细胞CLP群数量增多。同时造血干细胞向髓系共同祖细胞CMP及髓系发育受到抑制，并进一步通过骨髓移植证明了Pcid2调控造血干细胞向CLP方向发育是细胞内因性作用。本项目揭示了Pcid2调控MPP向CLP细胞谱系发育的分子机制依赖于SRCAP复合物染色质重塑活性对CLP谱系发育基因的转录调控作用。发现PCID2蛋白在MPP细胞中与SRCAP染色质重塑复合物重要的活性调节亚基ZNHIT1相互作用。确认PCID2与ZNHIT1的结合阻断了SRCAP的活性，抑制了组蛋白变体H2A.Z及淋巴谱系发育重要的转录因子PU.1对淋巴谱系特异基因的转录开放作用。本项目还进一步通过基因敲除确认了ZNHIT1对MPP向淋巴谱系发育和淋巴谱系基因转录的重要作用。本项目阐明了Pcid2在骨髓MPP特异向CLP谱系分化的过程中的重要调控作用，探明了PCID2与SRCAP重塑复合体组分之间的相互作用方式，揭示了PCID2协同SRCAP染色质重塑复合物及转录因子PU.1对淋巴谱系发育基因表达的表观调控机制，加深了对血液细胞谱系发育分化的认识。