Increased expression of PcG protein YY1 negatively regulates B cell development while allowing accumulation of myeloid cells and LT-HSC cells.
Increased expression of PcG protein YY1 negatively regulates B cell development while allowing accumulation of myeloid cells and LT-HSC cells.
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DOI：
10.1371/journal.pone.0030656
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Atchison ML
中科院分区：
文献类型：
--
作者：
Pan X;Jones M;Jiang J;Zaprazna K;Yu D;Pear W;Maillard I;Atchison ML
盈阳1 （YY1）是一种多功能Polycomb Group （PcG）转录因子，可结合免疫球蛋白（Ig）位点的多个增强子结合位点，在早期B细胞发育中起重要作用。PcG蛋白在造血干细胞更新中具有重要功能，YY1是唯一具有DNA结合特异性的哺乳动物PcG蛋白。在小鼠B细胞谱系中，YY1的条件敲除导致前B细胞阶段的阻滞，并且在不同YY1表达水平下观察到剂量效应。为了研究YY1表达升高对造血发育的影响，我们利用小鼠体内骨髓重建系统。我们发现，当小鼠骨髓细胞从造血干细胞/祖细胞发展到前B、前B、未成熟B和再循环B细胞阶段时，表达YY1水平升高的小鼠骨髓细胞表现出选择性劣势，但在髓系细胞中没有观察到YY1过表达的劣势。此外，表达YY1水平升高的小鼠骨髓细胞显示出具有长期造血干细胞（HSC）特征的表面标记细胞的富集。YY1的表达在体外诱导小鼠B细胞系凋亡，导致抗凋亡基因Bcl-xl和NFκB2的表达下调，而在小鼠髓系中未见影响。YY1诱导的B细胞凋亡和LT-HSC富集表明，诱导YY1表达的新策略可能在保护正常hsc的同时，对B系恶性肿瘤的治疗有有益的作用。
Ying Yang 1 (YY1) is a multifunctional Polycomb Group (PcG) transcription factor that binds to multiple enhancer binding sites in the immunoglobulin (Ig) loci and plays vital roles in early B cell development. PcG proteins have important functions in hematopoietic stem cell renewal and YY1 is the only mammalian PcG protein with DNA binding specificity. Conditional knock-out of YY1 in the mouse B cell lineage results in arrest at the pro-B cell stage, and dosage effects have been observed at various YY1 expression levels. To investigate the impact of elevated YY1 expression on hematopoetic development, we utilized a mouse in vivo bone marrow reconstitution system. We found that mouse bone marrow cells expressing elevated levels of YY1 exhibited a selective disadvantage as they progressed from hematopoietic stem/progenitor cells to pro-B, pre-B, immature B and re-circulating B cell stages, but no disadvantage of YY1 over-expression was observed in myeloid lineage cells. Furthermore, mouse bone marrow cells expressing elevated levels of YY1 displayed enrichment for cells with surface markers characteristic of long-term hematopoietic stem cells (HSC). YY1 expression induced apoptosis in mouse B cell lines in vitro, and resulted in down-regulated expression of anti-apoptotic genes Bcl-xl and NFκB2, while no impact was observed in a mouse myeloid line. B cell apoptosis and LT-HSC enrichment induced by YY1 suggest that novel strategies to induce YY1 expression could have beneficial effects in the treatment of B lineage malignancies while preserving normal HSCs.
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