Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiation
Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiation
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DOI：
10.1002/eji.200425469
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发表时间：
2004-12-01
影响因子：
5.4
通讯作者：
Merkenschlager, M
中科院分区：
文献类型：
--
作者：
Hewitt, SL;High, FA;Merkenschlager, M
为了研究在Th1和Th2细胞分化过程中基因表达的可遗传模式是如何获得的，我们利用三维荧光原位杂交技术分析了谱系限制性细胞因子基因及其上游调控因子的核位置。在Th1分化过程中，编码Th2细胞因子上游调控因子的GATA-3和c-maf位点逐渐被重新定位为由γ -卫星重复探针和/或核外周所定义的着丝异质，这些区室与转录抑制有关。控制th1特异性程序的第三个转录因子位点T-bet在Th2细胞克隆中受到从头CpG甲基化的影响。相反，我们没有发现细胞因子基因位点IL-2、IL-3、IL-4或ifn - γ在辅助性T细胞分化过程中的重新定位。相反，即使在Th1细胞中启动表达，ifn - γ也与核外周结构相关。我们的研究结果表明，Th1/Th2谱系的承诺和分化涉及细胞因子表达调节因子的重新定位，而不是细胞因子基因本身。
To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a gamma-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-gamma during T helper cell differentiation. Instead, IFN-gamma was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves.