Responses of MHC Class I Genes to Exogeneous Stimuli

MHC I类表达受组织特异性和激素调节机制的影响。MHC I类的表达受到多种刺激的动态调节。诸如TNF和干扰素之类的药物是众所周知的I类转录诱导剂。相反，促甲状腺激素（TSH）特异性地降低甲状腺细胞中I类基因的转录；这种下调是camp介导的。先前的实验室研究主要关注甲状腺中tsh介导的抑制机制，而最近的研究则通过转录共激活因子CIITA和T细胞特异性I类表达来研究干扰素介导的I类诱导的分子机制。CIITA共激活因子对MHC II类基因的转录激活至关重要，并介导MHC I类转录的增强。激活完全依赖于上游的CRE，位于-100和-107 bp之间，但进一步增强了一系列上游序列元素。有趣的是，CIITA介导激活的核心启动子要求与构成型转录的要求不同。此外，CIITA激活所需的转录因子也不同于构成型转录：构成型转录需要TAF1，而CIITA激活则不需要。激活转录和组成型转录的不同要求导致了转录起始位点的选择性使用：激活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。在不同组织中表达水平也有很大差异，在淋巴细胞室、T细胞和B细胞中，I类表达水平最高。虽然已知B细胞中的高I类表达涉及含有ciita的B细胞增强体，但尚未探索T细胞中高组成型I类表达的分子基础。由于T细胞特异性基因，如T细胞受体基因，受由RUNX1、CBF&#946；、LEF1和Aly组成的T细胞增强体（TCE）调控，我们想知道它是否同样调控I类基因。我们发现MHC I类基因的表达被TCE增强，这是含runx1复合物与体内I类基因相互作用的结果，表明TCE直接控制T细胞中I类基因的水平。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）途径起作用（即TAF-1依赖性）。这些发现为T细胞中组成性高水平的MHC I类提供了分子基础。相比之下，CIITA介导的&#947；-干扰素激活I类转录通过一个由一系列不同的因子组成的增强体起作用，即RFX、RFY和ATF/CREB，并针对不同的上游元件。TCE和CIITA的作用是协同的，表明两种信号通路在启动子处整合。

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.