Department of Life Science, Sogang University, Seoul, Korea 121-742.
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):276-81. doi: 10.1073/pnas.1214682110. Epub 2012 Dec 17.
The Th2 locus control region (LCR) has been shown to be important in efficient and coordinated cytokine gene regulation during Th2 cell differentiation. However, the molecular mechanism for this is poorly understood. To study the molecular mechanism of the Th2 LCR, we searched for proteins binding to it. We discovered that transcription factor YY1 bound to the LCR and the entire Th2 cytokine locus in a Th2-specific manner. Retroviral overexpression of YY1 induced Th2 cytokine expression. CD4-specific knockdown of YY1 in mice caused marked reduction in Th2 cytokine expression, repressed chromatin remodeling, decreased intrachromosomal interactions, and resistance in an animal model of asthma. YY1 physically associated with GATA-binding protein-3 (GATA3) and is required for GATA3 binding to the locus. YY1 bound to the regulatory elements in the locus before GATA3 binding. Thus, YY1 cooperates with GATA3 and is required for regulation of the Th2 cytokine locus and Th2 cell differentiation.
Th2 细胞定位控制区（LCR）在 Th2 细胞分化过程中高效协调细胞因子基因调控方面发挥着重要作用。然而，其分子机制尚不清楚。为了研究 Th2 LCR 的分子机制，我们寻找与其结合的蛋白。我们发现转录因子 YY1 以 Th2 细胞特异性的方式结合到 LCR 和整个 Th2 细胞因子基因座上。逆转录病毒过表达 YY1 可诱导 Th2 细胞因子表达。在小鼠中特异性敲低 CD4 上的 YY1 可显著减少 Th2 细胞因子表达，抑制染色质重塑，减少染色体间相互作用，并在哮喘动物模型中产生抗性。YY1 与 GATA 结合蛋白-3（GATA3）发生物理结合，并且是 GATA3 结合到基因座所必需的。YY1 在 GATA3 结合之前与基因座上的调控元件结合。因此，YY1 与 GATA3 合作，是调节 Th2 细胞因子基因座和 Th2 细胞分化所必需的。
