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BSAP Can Repress Enhancer Activity by Targeting PU.1 Function

机译：BSAP可以通过靶向PU.1功能抑制增强子活性

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摘要

PU.1 and BSAP are transcription factors crucial for proper B-cell development. Absence of PU.1 results in loss of B, T, and myeloid cells, while absence of BSAP results in an early block in B-cell differentiation. Both of these proteins bind to the immunoglobulin κ chain 3′ enhancer, which is developmentally regulated during B-cell differentiation. We find here that BSAP can repress 3′ enhancer activity. This repression can occur in plasmacytoma lines or in a non-B-cell line in which the enhancer is activated by addition of the appropriate enhancer binding transcription factors. We show that the transcription factor PU.1 is a target of the BSAP-mediated repression. Although PU.1 and BSAP can physically interact through their respective DNA binding domains, this interaction does not affect DNA binding. When PU.1 function is assayed in isolation on a multimerized PU.1 binding site, BSAP targets a portion of the PU.1 transactivation domain (residues 7 to 30) for repression. The BSAP inhibitory domain (residues 358 to 385) is needed for this repression. Interestingly, the coactivator protein p300 can eliminate this BSAP-mediated repression. We also show that PU.1 can inhibit BSAP transactivation and that this repression requires PU.1 amino acids 7 to 30. Transfection of p300 resulted in only a partial reversal of PU.1-mediated repression of BSAP. When PU.1 function is assayed in the context of the immunoglobulin κ chain 3′ enhancer and associated binding proteins, BSAP represses PU.1 function by a distinct mechanism. This repression does not require the PU.1 transactivation or PEST domains and cannot be reversed by p300 expression. The possible roles of BSAP and PU.1 antagonistic activities in hematopoietic development are discussed.
机译：PU.1和BSAP是对B细胞正常发育至关重要的转录因子。缺少PU.1会导致B，T和髓样细胞丢失，而缺少BSAP则会导致B细胞分化的早期阻滞。这两种蛋白质均与免疫球蛋白κ链3'增强子结合，后者在B细胞分化过程中受到发育调节。我们在这里发现BSAP可以抑制3'增强子活性。这种抑制作用可以发生在浆细胞瘤系或非B细胞系中，其中通过添加适当的增强子结合转录因子来激活增强子。我们表明转录因子PU.1是BSAP介导的镇压的目标。尽管PU.1和BSAP可以通过它们各自的DNA结合域进行物理相互作用，但是这种相互作用不会影响DNA的结合。当在多聚的PU.1结合位点上单独测定PU.1功能时，BSAP靶向PU.1反式激活结构域的一部分（残基7至30）以进行抑制。该抑制需要BSAP抑制域（残基358至385）。有趣的是，共激活蛋白p300可以消除这种BSAP介导的抑制作用。我们还表明，PU.1可以抑制BSAP反式激活，并且这种阻抑需要PU.1氨基酸7到30。p300的转染仅导致PU.1介导的BSAP阻抑的部分逆转。在免疫球蛋白κ链3'增强子和相关结合蛋白的背景下测定PU.1功能时，BSAP通过独特的机制抑制PU.1功能。这种抑制不需要PU.1反式激活或PEST结构域，并且不能被p300表达逆转。讨论了BSAP和PU.1拮抗活性在造血发育中的可能作用。

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