GENOMIC CHARACTERISTICS OF ARGONAUTE PROTEINS MEDIATE GENES CONTAINING LINE-1 EXPRESSION

Abstract

There is increasing evidence that transcriptionally active LINE-1 (L1) could have been co-opted through mammalian genomes evolution to play various roles including X-inactivation, homologous recombination and gene regulation. In this dissertation, both statistical and bioinformatic methods were used to evaluate intragenic L1 hypomethylation, which may influences their host gene expressions. All experiments utilized array data from the Gene Expression Omnibus (GEO) database and L1 information from L1Base. Genome-wide statistical analysis between genes containing L1s and their corresponding expression profile showed that these genes are likely to be repressed in both cancer and hypomethylated normal cells. Furthermore, AGO2 potentially forms a complex with intronic L1 pre-mRNA that correlates with the down-regulation of cancer genes. Thus, hypomethylated intragenic L1s could act as a nuclear siRNA mediated cis-regulatory element that can repress genes. Moreover, we found that intragenic L1 sequences have been conserved across evolutionary time with respect to transcriptional activity in human and mouse. The monomers located in the 5' UTR of mouse L1 (more monomers found more in intragenic regions of the host genome) suggesting their important role for controlling L1 expression. We then compared L1 distributions of both species across autosomes, X and Y chromosomes. The results agreeably reveal that L1 densities of both species located much denser in the X-chromosome, suggestive of X-inactivation role. A significant correlation was demonstrated between the presence of intragenic L1s and downregulated genes in the early embryogenesis of both species, suggestive of a similar role in regulating genes in cancers.