Chromatin remodeling by the T cell receptor (TCR)-beta gene enhancer during early T cell development: Implications for the control of TCR-beta locus recombination.
Chromatin remodeling by the T cell receptor (TCR)-beta gene enhancer during early T cell development: Implications for the control of TCR-beta locus recombination.
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DOI：
10.1084/jem.192.5.625
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发表时间：
2000-09-04
期刊：
影响因子：
--
通讯作者：
Ferrier P
中科院分区：
文献类型：
--
作者：
Mathieu N;Hempel WM;Spicuglia S;Verthuy C;Ferrier P
基因打靶研究表明，在T细胞受体（TCR）-β基因座3′端缺失一个增强子（Eβ）后，TCR-β基因的表达和重组受到抑制。使用基因敲除小鼠模型，我们在TCR-β基因座的不同区域测量了Eβ缺失对分子参数的影响，这些分子参数被认为反映了与基因激活控制相关的表观遗传变化，包括限制性内切酶进入染色体DNA、种系转录、DNA甲基化和组蛋白H3乙酰化。我们的研究结果表明，在早期发育的胸腺细胞中，Eβ参与了主要的染色质重塑，该重塑指向由Dβ-Jβ基因座区域组成的约25-kb上游结构域。因此，用组蛋白去乙酰化酶抑制剂利司他汀A处理Eβ缺失的胸腺细胞，缓解了TCR-β基因表达的阻断，并促进了Dβ-Jβ基因座内的重组。然而，出乎意料的是，在该基因座5′侧的远端Vβ基因和3′近端Vβ14基因的表观遗传过程似乎对Eβ的依赖性较低，表明Eβ活性仅限于TCR-β基因座的离散区域。这些发现对于TCR-β基因重组的发育控制以及该位点的等位基因排斥过程具有意义。
Gene targeting studies have shown that T cell receptor (TCR)-β gene expression and recombination are inhibited after deletion of an enhancer (Eβ) located at the 3′ end of the ∼500-kb TCR-β locus. Using knockout mouse models, we have measured, at different regions throughout the TCR-β locus, the effects of Eβ deletion on molecular parameters believed to reflect epigenetic changes associated with the control of gene activation, including restriction endonuclease access to chromosomal DNA, germline transcription, DNA methylation, and histone H3 acetylation. Our results demonstrate that, in early developing thymocytes, Eβ contributes to major chromatin remodeling directed to an ∼25-kb upstream domain comprised of the Dβ-Jβ locus regions. Accordingly, treatment of Eβ-deleted thymocytes with the histone deacetylase inhibitor trichostatin A relieved the block in TCR-β gene expression and promoted recombination within the Dβ-Jβ loci. Unexpectedly, however, epigenetic processes at distal Vβ genes on the 5′ side of the locus and at the 3′ proximal Vβ14 gene appear to be less dependent on Eβ, suggesting that Eβ activity is confined to a discrete region of the TCR-β locus. These findings have implications with respect to the developmental control of TCR-β gene recombination, and the process of allelic exclusion at this locus.
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