Responses of MHC Class I Genes to Exogeneous Stimuli

点击翻译按钮获取中文摘要

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.