Regulation of Expression of MHC Class I Genes

MHC I 类基因表达的调节

• 批准号: 6950557
• 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/6950557
• 关键词: MHC class I antigen; gene induction /repression; genetic promoter element; genetic regulation; genetic transcription; histocompatibility gene; immunogenetics; nucleic acid sequence; transcription factor

Transcription of major histocompatibility complex (MHC) class I genes is regulated by both tissue-specific (basal) and hormone/cytokine (activated) mechanisms. Although promoter-proximal regulatory elements have been characterized extensively, the role of the core promoter in mediating regulation has been largely undefined. We have found that the class I core promoter consists of distinct elements that are differentially utilized in basal and activated transcription pathways. These pathways recruit distinct transcription factor complexes to the core promoter elements and target distinct transcription initiation sites. Class I transcription initiates at four major sites within the core promoter and is clustered in two distinct regions: "upstream" (-14 and -18) and "downstream" (+12 and +1). Basal transcription initiates predominantly from the upstream start site region and is completely dependent upon the general transcription factor TAF1 (TAF(II)250). Activated transcription initiates predominantly from the downstream region and is TAF1 (TAF(II)250)independent. USF1 augments transcription initiating through the upstream start sites and is dependent on TAF1 (TAF(II)250), a finding consistent with its role in regulating basal class I transcription. In contrast, transcription activated by the interferon mediator CIITA is independent of TAF1 (TAF(II)250) and focuses initiation on the downstream start sites. Thus, both in vivo and in vitro, basal and activated transcriptions of an MHC class I gene target distinct core promoter domains, nucleate distinct transcription initiation complexes and initiate at distinct sites within the promoter. We have proposed that transcription initiation at the core promoter is a dynamic process in which the mechanisms of core promoter function differ depending on the cellular environment.

主要组织相容性复合体（MHC）I类基因的转录受组织特异性（基础）和激素/细胞因子（激活）机制的调节。虽然启动子近端调控元件已被广泛表征，但核心启动子在介导调控中的作用在很大程度上尚未确定。我们已经发现，I类核心启动子由不同的元件组成，这些元件在基础和激活的转录途径中被不同地利用。这些途径将不同的转录因子复合物募集到核心启动子元件并靶向不同的转录起始位点。I类转录起始于核心启动子内的四个主要位点，并聚集在两个不同的区域：“上游”（-14和-18）和“下游”（+12和+1）。基础转录主要从上游起始位点区域开始，并且完全依赖于通用转录因子TAF 1（TAF（II）250）。激活的转录主要从下游区域开始，并且不依赖于TAF 1（TAF（II）250）。USF 1通过上游起始位点增强转录起始，并依赖于TAF 1（TAF（II）250），这一发现与其在调节基础I类转录中的作用一致。相反，由干扰素介体CIITA激活的转录不依赖于TAF 1（TAF（II）250），并将起始集中在下游起始位点。因此，在体内和体外，MHC I类基因的基础和活化转录靶向不同的核心启动子结构域，使不同的转录起始复合物成核，并在启动子内的不同位点起始。我们已经提出，在核心启动子的转录起始是一个动态的过程中，核心启动子功能的机制取决于细胞环境的不同。