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-近端调控元件已被广泛描述，但核心启动子在调节调控中的作用在很大程度上尚未定义。我们发现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被不同地利用。这些途径将不同的转录因子复合物招募到核心启动子元件并靶向不同的转录起始位点。I类转录在核心启动子的四个主要位点启动，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，完全依赖于通用转录因子TAF1 （TAF(II)250）。激活转录主要从下游区域启动，并且与TAF1 （TAF(II)250）无关。在体内和体外，MHC I类基因的基础转录和激活转录靶向不同的核心启动子结构域，形成不同的转录起始复合物，并在启动子内的不同位点启动。我们定义了一种新的核心启动子特征，允许在转录起始位点（TSS）选择水平上调控MHC I类基因PD1的转录。由于在真正的起始ATG上游约450 bp内没有任何ATG三联体，多个分散的TSS编码一个蛋白质。因此，PD1核心启动子嵌入在“ATG沙漠”中。值得注意的是，将这一分析扩展到全基因组，我们发现ATG沙漠发生非随机，最值得注意的是与非tataa启动子相关，独立于CpG岛（cgi）的存在。我们进一步证明了多个转录起始位点的使用与非tataa启动子之间的显著相关性。我们推测ATG沙漠确保具有多个TSS的启动子不会直接合成异常蛋白产物，从而使它们能够作为整合复杂上游调控信号的平台。我们提出核心启动子的转录起始是一个动态过程，其中核心启动子的功能机制因细胞环境而异。

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. 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 defined a novel core promoter feature that permits regulated transcription of the MHC class I gene, PD1, at the level of transcript start site (TSS) selection. The multiple, dispersed TSS encode a single protein, due to the absence of any ATG triplets within approximately 450 bp upstream of the authentic initiator ATG. Thus, the PD1 core promoter is embedded within an "ATG desert". Remarkably, extending this analysis genome-wide, we find that ATG deserts occur non-randomly and most notably are associated with non-TATAA promoters, independent of the presence of CpG islands (CGIs). We further document a significant correlation between the use of multiple transcription start sites and non-TATAA promoters. We speculate that ATG deserts ensure that promoters with multiple TSS do not direct synthesis of aberrant protein products, thereby permitting them to serve as a platform to integrate complex upstream regulatory signals. 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.