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。尽管启动子近端调节元件已被广泛表征，但核心启动子在介导调节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）。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。我们已经定义了一个新的核心启动子功能，允许调节转录的MHC I类基因，PD1，在转录起始位点（TSS）的选择水平。多个分散的TSS编码单个蛋白质，这是由于在真实起始子ATG上游约450 bp内不存在任何ATG三联体。因此，PD1核心启动子嵌入"ATG沙漠"内。值得注意的是，将这种分析扩展到全基因组，我们发现ATG沙漠非随机发生，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和非TATAA启动子的使用之间的显著相关性。我们推测，ATG沙漠确保启动子与多个TSS不指导异常蛋白质产物的合成，从而允许它们作为一个平台，整合复杂的上游调控信号。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。

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.