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: 8348928
• 负责人: Dinah S. Singer
• 金额: $ 35万
• 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/8348928
• 关键词: Acetyltransferase; Affect; Autoantigens; Autoimmune Diseases; Binding; Cell Surface Receptors; Complex; Critical Pathways; Data; Disease; Failure; Genes; Genetic Transcription; Goals; HIV; Hormones; Immune response; Immunologic Surveillance; Inflammation; Interferon Type II; Interferons; Lead; MHC Class I Genes; MHC Class II Genes; Major Histocompatibility Complex; Mediating; Molecular; Molecular Profiling; Pathway interactions; Peptides; Play; Regulatory Pathway; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stimulus; TAF1 gene; TAF7 gene; Tissues; Transcript; Transcription Initiation; Tumor Antigens; base; carcinogenesis; cytokine; extracellular; neoplastic cell; pathogen; programs; promoter; response; tumor

The TFIID components TAF7 and TAF1 regulate eukaryotic transcription initiation. TAF7 regulates transcription initiation of TAF1-dependent genes by binding to the acetyltransferase (AT) domain of TAF1 and inhibiting the enzymatic activity that is essential for transcription. TAF7 is released from the TAF1/TFIID complex upon completion of preinitiation complex assembly, allowing transcription to initiate. However, not all transcription is TAF1-dependent and the role of TAF7 in regulating TAF1-indepedent transcription has not been defined. The IFN-gamma--induced transcriptional co-activator CIITA activates MHC class I and class II genes, which are vital for immune responses, in a TAF1 independent manner. Activation by CIITA depends on its intrinsic AT activity. We now show that TAF7 binds to CIITA and inhibits its AT activity, thereby repressing activated transcription. Consistent with this TAF7 function, siRNA-mediated depletion of TAF7 results in increased CIITA-dependent transcription. A more global role for TAF7 as a regulator of transcription was revealed by expression profiling analysis: expression of 30-40% of genes affected by TAF7 depletion was independent of either TAF1 or CIITA. Surprisingly, while TAF1-dependent transcripts are largely down-regulated by TAF7-depletion, TAF1-independent transcripts are predominantly up-regulated. We conclude that TAF7, until now considered only a TFIID component and regulator of TAF1-dependent transcription, also regulates TAF1-independent transcription.

TFIID组件TAF7和TAF1调节真核转录启动。 TAF7通过与TAF1的乙酰转移酶（AT）结合并抑制转录必不可少的酶促活性来调节TAF1依赖性基因的转录启动。 TAF7在完成前的复合体组装后从TAF1/TFIID复合物中释放出来，从而启动转录。但是，并非所有转录都是taf1依赖性的，并且尚未定义TAF7在调节TAF1内部转录中的作用。 IFN-GAMMA诱导的转录共激活因子CIITA激活MHC I类和II类基因，这对于以TAF1独立的方式对免疫反应至关重要。 CIITA的激活取决于其在活性的固有性。现在，我们表明TAF7与CIITA结合并抑制其AT活性，从而抑制活化的转录。与该TAF7函数一致，siRNA介导的TAF7的耗竭导致CIITA依赖性转录增加。通过表达分析分析揭示了TAF7作为转录调节剂的更全球作用：30-40％受TAF7耗竭影响的基因的表达与TAF1或CIITA无关。出乎意料的是，尽管TAF1依赖性转录本在很大程度上被TAF7止动物下调，但TAF1独立的转录本主要是上调的。我们得出的结论是，直到现在，TAF7仅考虑了TFIID成分和TAF1依赖性转录的调节剂，还调节了TAF1独立的转录。