Lee Kyoo Y, Choi Young I, Kim Jieun, Choi Jin W, Sohn Dong H, Lee Changjin, Jeon Sung H, Seong Rho H
Department of Biological Sciences, Institute of Molecular Biology and Genetics, and Research Center for Functional Cellulomics, Seoul National University, Seoul, Korea.
J Immunol. 2007 Jun 1;178(11):7088-96. doi: 10.4049/jimmunol.178.11.7088.
The process of thymocyte development requires an exquisite regulation of many genes via transcription factors and chromatin remodeling activities. Even though the SWI/SNF chromatin remodeling complex has been thought to play important roles during thymocyte development, its known function is very limited. In this study, we show that the SWI/SNF chromatin remodeling activity is finely regulated during thymocyte maturation process, especially during thymocyte selections. We found that TCR signaling directly down-regulates mBRG1 and SWI3-related gene, the core components of murine SWI/SNF complex, during thymocyte maturation. Constitutive expression of SWI3-related gene in developing thymocytes attenuated the down-regulation of the SWI/SNF complex and resulted in a change in the expression of genes such as linker for activation of T cells and casitas B lineage lymphoma, which affected the TCR-mediated intracellular signaling pathway. The defects in TCR signaling resulted in the disruption of both positive and negative selections in specific TCR transgenic mice systems. Our results state, for the first time, that the chromatin remodeling activity needs to be finely controlled for proper thymocyte selection and maturation processes.
胸腺细胞发育过程需要通过转录因子和染色质重塑活动对众多基因进行精确调控。尽管SWI/SNF染色质重塑复合体被认为在胸腺细胞发育过程中发挥重要作用，但其已知功能非常有限。在本研究中，我们表明SWI/SNF染色质重塑活性在胸腺细胞成熟过程中，尤其是在胸腺细胞选择过程中受到精细调控。我们发现，在胸腺细胞成熟过程中，TCR信号直接下调小鼠SWI/SNF复合体的核心成分mBRG1和SWI3相关基因。在发育中的胸腺细胞中组成性表达SWI3相关基因可减弱SWI/SNF复合体的下调，并导致诸如T细胞活化连接蛋白和卡斯他B系淋巴瘤等基因表达发生变化，这影响了TCR介导的细胞内信号通路。TCR信号缺陷导致特定TCR转基因小鼠系统中阳性和阴性选择均被破坏。我们的结果首次表明，为了胸腺细胞的正常选择和成熟过程，染色质重塑活性需要受到精细控制。
