| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 98 === It is well-known that genes in prokaryotes are arranged in short proximity and organized in an operonic architecture for effective co-expression and co-regulation. Corresponding studies in eukaryotes, however, no such operonic structure was found in complex loci of mammalian genomes. To examine whether there are similar operon-like organizations in mammalian genomes, I characterized and separated all the relative orientations of the human 35,306 and mouse 33,729 genes into four types of gene-pair organizations, defined as the nearest gene neighbors. Significantly, 17.5% of genes were found to be closely adjacent in a divergent manner with only less than 1,000-bp apart from each other, indicating that the head-to-head gene pairs are a common feature of mammalian genomes. Functionally, many of these head-to-head gene pairs were identified to participate in key physiological functions such as oxidative phosphorylation and DNA repair. Those findings suggested that the conserved head-to-head gene organizations, abundant in human and mouse genomes, contain an undiscovered exquisite mechanism to regulate series functional related genes based on the shared transcribed regions. The results also shed new insight to the novel bidirectional regulation in the complex loci of mammalian genomes. To more clarify the regulatory mechanism of bidirectional gene pair, I deeply investigate an evolutionarily conserved bidirectional gene pair, known as the PREPL-C2ORF34 gene pair. While PREPL is present primarily in brain and heart, C2ORF34 is ubiquitously and abundantly expressed in almost all tissues. Genomic analyses revealed that these two non-homologous genes are adjacent in a head-to-head configuration on human chromosome 2p21 and separated by only 405 bp. Within this short intergenic region, a 243-bp of GC-rich segment was demonstrated to function as a bidirectional minimal promoter to initiate the transcription of both flanking genes. Two key transcriptional factors, NRF-2 and YY1, were further identified to coordinately participate in driving both gene expressions in an additive manner. The functional cooperation between these two transcription factors, along with their genomic binding sites and some cis-acting repressive elements, are essential for the transcriptional activation and tissue distribution of the PREPL-C2ORF34 bidirectional gene pair. This study provides new insights into the complex transcriptional mechanism of an operon-like head-to-head organization in vertebrate and an exquisite bidirectional promoter for controlling the transcription of two adjacent genes.
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