Responses of MHC Class I Genes to Exogeneous Stimuli

MHC I类分子的表达受组织特异性和激素调节机制的影响。MHC I类分子的表达在各种刺激下受到动态调节。诸如TNF和干扰素的试剂是熟知的I类转录诱导剂。相反，促甲状腺激素（TSH）特异性降低甲状腺细胞中I类基因的转录;这种下调是cAMP介导的。而以前的研究在实验室中集中在TSH介导的抑制甲状腺的机制，最近的研究已经检查了通过转录共激活因子CIITA和T细胞特异性I类表达的干扰素介导的I类诱导的分子机制。CIITA共激活因子对于MHC II类基因的转录激活是必需的，并且介导增强的MHC I类转录。激活完全依赖于上游CRE，位于-100和-107 bp之间，但通过一系列上游序列元件进一步增强。有趣的是，CIITA介导的激活的核心启动子的要求是不同于那些组成型转录。此外，CIITA激活的转录因子要求也不同于组成型转录的要求：组成型转录需要TAF 1，而CIITA激活不需要。活化转录和组成型转录的不同要求导致转录起始位点的选择性使用：活化转录将转录集中在核心启动子内的下游位点，而组成型转录主要在上游位点。表达水平在组织中也有很大差异，最高水平的I类发生在淋巴区室、T细胞和B细胞中。虽然已知B细胞中I类高表达涉及含CIITA的B细胞增强体，但尚未探索T细胞中I类高组成性表达的分子基础。由于T细胞特异性基因，如T细胞受体基因，由RUNX 1，CBF，LEF 1和Aly组成的T细胞增强体（TCE）调节，我们已经询问了它是否类似地调节I类基因。我们发现，MHC I类基因的表达增强的TCE和结果从RUNX 1的复合物与I类基因在体内的相互作用，表明TCE直接管理的水平在T细胞中的I类。重要的是，尽管TCE介导高水平的I类表达，但它通过组织特异性（基础）途径（即TAF-1依赖性）发挥作用。这些发现为T细胞中MHC I类组成性高水平提供了分子基础。相比之下，由CIITA介导的α-干扰素激活I类转录通过由一组不同的因子，即RFX，RFY和ATF/CREB组成的增强体起作用，并靶向不同的上游元件。TCE和CIITA的作用是协同的，证明了两种信号传导途径在启动子处的整合。

MHC class I expression is subject to both tissue-specific and hormonal regulatory mechanisms. Expression of MHC class I is dynamically regulated in response to a variety of stimuli. Agents such as TNF and interferon are well known inducers of class I transcription. In contrast, thyroid stimulating hormone (TSH) specifically reduces class I gene transcription in thyrocytes; this down-regulation is cAMP-mediated. Whereas previous studies in the laboratory have focused on the mechanisms of TSH-mediated repression in the thyroid, recent studies have examined the molecular mechanisms regulating interferon-mediated induction of class I through the transcriptional co-activator CIITA and T cell specific class I expression. The CIITA co-activator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. Activation is absolutely dependent on the upstream CRE, located between -100 and -107 bp, but is further enhanced by a series of upstream sequence elements. Interestingly, the core promoter requirements for CIITA mediated activation are distinct from those of constitutive transcription. Furthermore, the transcription factor requirements for CIITA activation are also distinct from those of constitutive transcription: constitutive transcription requires TAF1 whereas CIITA activation does not. The distinct requirements of activated and constitutive transcription result in the selective usage of transcription start sites: activated transcription focuses transcription to downstream sites within the core promoter while constitutive transcription is primarily at upstream sites. Levels of expression also vary widely among tissues, with the highest levels of class I occurring in the lymphoid compartment, in T cells and B cells. While the high class I expression in B cells is known to involve the CIITA-containing B cell enhanceosome, the molecular basis for high constitutive class I expression in T cells has not been explored. Since T cell specific genes, such as T cell receptor genes, are regulated by a T cell enhanceosome (TCE) consisting of RUNX1, CBFβ, LEF1 and Aly, we have asked whether it similarly regulates class I genes. We found that MHC class I gene expression is enhanced by the TCE and results from an interaction of the RUNX1-containing complex with the class I gene in vivo, demonstrating that the TCE directly governs levels of class I in T cells. Importantly, although the TCE mediates high levels of class I expression, it functions through the tissue-specific (basal) pathway (i.e. TAF-1 dependent). These findings provide a molecular basis for the constitutively high levels of MHC class I in T cells. In contrast, the activation of class I transcription by γ-interferon mediated by CIITA functions through an enhanceosome consisting of a distinct set of factors, namely RFX, RFY and ATF/CREB and targets distinct upstream elements. The effects of the TCE and CIITA are synergistic, demonstrating integration of the two signaling pathways at the promoter.