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Who's the boss? an investigation into the complex relationship between endogenous retroviruses and nearby genes

University of British Columbia

Nearly half of the human and mouse genomes is composed of transposable elements (TEs) which are pieces of DNA capable of or once capable of moving to different locations in the genome. These mobile elements can potentially impact host gene expression in a variety of ways either directly through insertional mutagenesis or indirectly by serving as an alternative promoter/enhancer or through modification of splice signals. In order to protect the integrity of the genome, various mechanisms have evolved to silence TEs. Chromatin modifications, namely DNA methylation and histone modifications, represent two methods of transcriptional silencing of transposable elements. In previous studies it has been shown that methylation of short interspersed nucleotide element (SINE) TEs in the plant and mouse genome can “spread” into flanking sequences. I chose to investigate this “spreading” phenomenon with respect to endogenous retroviruses (ERVs) which are highly active in the mouse genome. Direct evidence has been provided for ERVs in the mouse genome inducing the spread of repressive chromatin. However, the ability of ERV-induced “spreading” to impact nearby gene expression has not yet been characterized. In my thesis, I provide evidence for repressive chromatin spreading as an infrequent occurrence with the exception of the B3galtl gene where DNA methylation and repressive histone marks spread from a solitary ERV long terminal repeat (LTR) into the CpG island promoter of the gene, which correlates with reduced gene transcription. In most cases, however, I show that CpG islands are unmethylated despite the presence of a nearby methylated ERV. Furthermore, I show examples of differential epigenetic marking of insertions with the 3’LTR of the insertion located closest to the nearby gene exhibiting hypomethylation. In one case in particular, I show an interesting trend between expression of the CdGAP gene and hypomethylation of the nearby 3’LTR. These results lead to the conclusion that susceptibility to or protection from “spreading” of repressive chromatin marks is a locus-specific event that may be mediated by various factors such as the ERV-gene distance, the presence of a CpG island gene promoter, the chromatin state of the gene promoter, and the expression of the corresponding gene.

Text

2011-10-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/38133

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/