Responses of MHC Class I Genes to Exogeneous Stimuli

MHC I 类基因对外源刺激的反应

• 批准号: 7048914
• 负责人: DINAH SINGER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7048914
• 关键词: MHC class I antigen; T cell receptor; T lymphocyte; gene expression; gene induction /repression; genetic enhancer element; genetic promoter element; genetic transcription; interferons; intermolecular interaction; nucleic acid sequence; transcription factor

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, recent studies are examining the molecular basis of interferon-mediated induction through the transcriptional co-activator CIITA. The CIITA co-activator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. Class I promoter activation by CIITA requires both the downstream core promoter and upstream sequences. 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 DNA sequence 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 TAFII250 whereas CIITA activation does not.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. T cell specific genes, such as T cell receptor genes, are regulated by a T cell enhanceosome consisting of RUNX1, CBF, LEF1 and Aly. In this report, we demonstrate that MHC class I gene expression is enhanced by the T cell enhanceosome and results from a direct interaction of the RUNX1-containing complex with the class I gene in vivo. T cell enhanceosome activation of class I transcription is synergistic with interferon- (IFN mediated activation and targets response elements distinct from those targeted by IFN These findings provide a molecular basis for the high levels of MHC class I in T cells.

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介导的抑制机制，最近的研究正在检查干扰素介导的诱导通过转录辅激活因子CIITA的分子基础。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。CIITA激活I类启动子需要下游核心启动子和上游序列。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DNA序列要求与组成型转录的DNA序列要求不同。此外，CIITA激活的转录因子要求也不同于组成型转录：组成型转录需要TAFII 250，而CIITA激活不需要。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。T细胞特异性基因，如T细胞受体基因，受由RUNX 1、CBF、LEF 1和Aly组成的T细胞增强体调节。在这份报告中，我们证明，MHC I类基因的表达增强的T细胞增强体和结果从一个直接的相互作用的RUNX 1的复合物与I类基因在体内。T细胞I类转录的增强体激活与干扰素-IFN介导的激活是协同的，并且靶向与IFN靶向的应答元件不同的应答元件。这些发现为T细胞中高水平的MHC I类提供了分子基础。