Regulation of Expression of MHC Class I Genes

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-近端调控元件已经被广泛地表征，但核心启动子在调节调节中的作用在很大程度上还不清楚。我们已经发现，I类核心启动子由不同的元件组成，这些元件在基础转录途径和激活转录途径中有不同的利用。这些途径招募不同的转录因子复合体到核心启动子元件，并靶向不同的转录起始点。I类转录起始于核心启动子内的四个主要位置，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区开始，完全依赖于通用转录因子TAF1(TAF(II)250)。激活的转录主要从下游区域开始，不依赖于TAF1(TAF(II)250)。USF1通过上游起始位点增强转录启动，并依赖于TAF1(TAF(II)250)，这一发现与其在调节基本I类转录中的作用一致。相反，由干扰素介导物CIITA激活的转录不依赖于TAF1(TAF(II)250)，而专注于下游起始位点的启动。因此，在体内和体外，MHC-I类基因的基础转录和激活转录都以不同的核心启动子区域为靶点，形成不同的转录起始复合体，并在启动子内的不同位置启动。我们提出核心启动子的转录启动是一个动态过程，核心启动子的作用机制因细胞环境的不同而不同。

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.