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首页> 外文期刊>Journal of Molecular Biology >PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity
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PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity

机译：PU.1 / Spi-1与人类TAL-1沉默子结合以介导其活性

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摘要

The TAL-1/SCL gene encodes a basic helix-loop-helix (bHLH) transcription factor essential for primitive hematopoiesis and for adult erythroid and megakaryocytic development. Activated transcription of TAL-1 as a consequence of chromosomal rearrangements is associated with a high proportion of human T cell acute leukemias, showing that appropriate control of TAL-1 is crucial for the formation and subsequent fate of hematopoietic cells. Hence, the knowledge of the mechanisms, which govern the pattern of TAL-1 expression in hematopoiesis, is of great interest. We previously described a silencer in the 3'-untranslated region of human TAL-1, the activity of which is mediated through binding of a tissue-specific 40 kDa nuclear protein to a new DNA recognition motif, named tal-RE. Here, we show that tal-RE-binding activity, high in immature human hematopoietic progenitors is down regulated upon erythroid and megakaryocytic differentiation. This expression profile helped us to identify that PU.1/Spi-1 binds to the tal-RE sequences in vitro and occupies the TAL-1 silencer in vivo. By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. We found that ectopic PU.1 is not able to induce silencing activity in PU.1-negative Jurkat T cells, indicating that PU.1 activity, although necessary, is not sufficient to confer transcriptional repression activity to the TAL-1 silencer. Finally, we showed that the silencer is also active in TAL-1-negative myeloid HL60 cells that express PU.1 at high levels. In summary, our study shows that PU.1, in addition to its positive role in TAL-1 expression in early hematopoietic progenitors, may also act as a mediator of TAL-1 silencing in some hernatopoietic lineages. (c) 2005 Elsevier Ltd. All rights reserved.
机译：TAL-1 / SCL基因编码一个基本的螺旋-环-螺旋（bHLH）转录因子，对于原始的造血功能以及成人的类红细胞和巨核细胞的发育至关重要。由于染色体重排而导致的TAL-1激活转录与高比例的人类T细胞急性白血病有关，这表明对TAL-1的适当控制对于造血细胞的形成和随后的命运至关重要。因此，对控制造血过程中TAL-1表达模式的机制的知识引起了极大的兴趣。我们之前在人类TAL-1的3'非翻译区描述了一个沉默子，该沉默子的活性是通过组织特异性40 kDa核蛋白与新的DNA识别基序tal-RE结合而介导的。在这里，我们表明，在未成熟的人类造血祖细胞中高的tal-RE-结合活性在红系和巨核细胞分化时被下调。该表达谱帮助我们鉴定出PU.1 / Spi-1在体外与tal-RE序列结合，并在体内占据TAL-1沉默子。通过在人类红白血病HEL细胞中表达仅包含PU.1的ETS域的突变蛋白，我们证明了PU.1介导了沉默子的转录抑制活性。我们发现异位PU.1不能诱导PU.1阴性Jurkat T细胞中的沉默活性，这表明PU.1活性尽管必要，但不足以赋予TAL-1沉默子转录抑制活性。最后，我们证明了该沉默子在高表达PU.1的TAL-1阴性髓样HL60细胞中也具有活性。总之，我们的研究表明，PU.1除了在早期造血祖细胞中TAL-1表达中发挥积极作用外，还可能在某些造血细胞谱系中充当TAL-1沉默的介体。 （c）2005 Elsevier Ltd.保留所有权利。

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