Epigenetic regulation of the human genome by transposable elements

Transposable elements (TEs) are repetitive DNA sequences that can move from one location in the genome to another. I studied the relationship between TEs and the human genome vis-a-vis epigenetic mechanisms and the extent to which TEs contribute to the epigenetic regulation of the human genome.;Research advance 1. In chapter 2, various tools and methods to discover and annotate TEs in eukaryotic genomes are evaluated. Commonly used tools CENSOR and RepeatMasker are compared using different metrics [6,7]. Both of these programs use a reference library of TE sequences for annotation. A discussion is provided at the end of this chapter that details the advantages and disadvantages of using reference based versus de novo methods for TE annotation.;Research advance 2. In chapter 3, the current state of understand of the relationship between TEs and various epigenetic mechanisms is deliberated. Historical perspectives of the role of TEs in the evolution of the eukaryotic genomes are presented and the need to investigate the relationship between extant TEs and epigenetic mechanisms is elaborated. Finally a road map that aims to elucidate the contribution of TEs in the epigenetic regulation of the human genome using models of nucleosome binding as well as high-throughput epigenetic data, is presented.;Research advance 3. Chapter 4 discusses the role of TEs in regulating gene expression via nucleosome binding. Promoter regions of human genes display a particular distribution of TEs as well as Simple Sequence Repeats (SSRs). The distribution of TEs is closely related to the pattern of nucleosome binding in the promoter regions. Indeed, nucleosome binding affinity is strongly positively correlated with TE density and strongly negatively correlated to SSR density in the promoter regions. Nucleosome binding affinity of the promoter regions affects the accessibility of promoter DNA to DNA binding proteins and is thus implicated in the regulation of gene expression. The relationship between the TE profile of promoters and the expression of their respective genes is also investigated.;Research advance 4. Chapter 5 evaluates the global landscape of several histone modifications in human CD4+ T-cells with respect to two competing hypotheses: Genome defense and exaptation. Genome defense postulates that epigenetic mechanisms such as histone modifications serve primarily to suppress the activity of TEs whereas exaptation entails that TEs are epigenetically modified in such a way as to allow them to be utilized by the human genome to serve its regulatory or coding needs. Specific predictions from each of these hypotheses are tested using epigenetic data and the results offer more support to the exaptation model than the genome defense model.;Research advance 5. In chapter 6, the extent to which TEs contribute transcriptional start site and promoter sequences to the human genome is investigated. Hundreds of transcriptional start sites of human genes originate in TEs and these TE-derived promoter genes are epigenetically regulated in accordance with their function in the specific cell type. TE-derived promoters are involved in epigenetically regulating cell type specific expression of these genes in two human hematopoietic cell lines, GM12878 and K562. A substantial fraction of these genes is also differentially modified and expressed between the two cell lines as per their role in cell type specific function. The role of TEs in epigenetically regulating gene expression in various human cell types is also discussed.;Research advance 6. Chapter 7 explores the contribution of TEs in donating enhancer sequences that epigenetically regulate the expression of human genes in a cell type specific manner. Experimentally characterized enhancers display a specific pattern of enrichment of various histone modifications and this pattern is used in a computational approach to guide the search for novel enhancers in the GM12878 and K562 cell lines. Using epigenetic histone modification data in the two cell lines, this approach yielded several hundred enhancers donated by TEs in each cell line. The functional effect of these enhancers on regulating cell type specific expression of nearby genes is also investigated. (Abstract shortened by UMI.)...