REGULATION OF EXPRESSION OF CLASS I MHC GENE

I 类 MHC 基因表达的调节

• 批准号: 3808602
• 负责人: D SINGER
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 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/3808602
• 关键词: MHC class I antigen; gene expression; genetic enhancer element; genetic operator element; genetic promoter element; genetically modified animals; laboratory mouse; major histocompatibility complex; nucleic acid sequence; transcription factor

MHC class I genes encoding transplantation antigens are ubiquitously expressed, although their level of expression varies among tissues. Analysis of the 5' flanking DNA sequences of a swine class I gene has demonstrated that in addition to the canonical promoter, this region contains a series of negative and positive regulatory elements. One of the regulatory elements (RE-140) associated with this gene consists of overlapping negative and positive elements. Introduction into transgenic mice of a series of nested deletions containing a common 3' terminus, but differing in the extent of 5' flanking regulatory sequences, reveals that this complex regulatory element functions in a tissue specific manner, such that the enhancer activity predominates in lymphoid tissues, but not in non-lymphoid tissues. Another negative regulatory element, RE-105, has been identified which is distinct from RE-140 in both sequence and function. In transgenic animals, RE105 functions as a silencer in all tissues examined. The silencer component of RE-140 has been shown to have striking similarities to the yeast mating type repression system. A moderate DNA sequence homology exists between the yeast and mammalian operators. Mammalian factors bind to the yeast alpha2 operator and also specifically interact with a yeast alpha2-binding protein. Further, the yeast alpha2 operator functions as a silencer element in mammalian cells when placed upstream of a MHC class I promoter. All of the functionally identified regulatory elements are associated with trans acting factors. RE-140 DNA forms distinct enhancer and silencer associated complexes with cellular factors. Each consists of at least two distinct factors. Analysis of binding activity from a variety of cell lines and tissues reveals that RE-140 enhancer binding activity is present in all extracts, independent of the level of class I expression. The level of RE-140 silencer binding activity is inversely proportion to the level of class I gene expression. These studies have led to the proposal that class I genes are negatively regulated.

编码移植抗原的MHC I类基因无处不在