Abstract
Transposable Elements (TEs) have long been regarded as selfish or junk DNA having little or no role in the regulation or functioning of the human genome. However, over the past several years this view came to be challenged as several studies provided anecdotal as well as global evidence for the contribution of TEs to the regulatory and coding needs of human genes. In this study, we explored the incorporation and epigenetic regulation of coding sequences donated by TEs using gene expression and other ancillary genomics data from two human hematopoietic cell-lines: GM12878 (a lymphoblastoid cell line) and K562 (a Chronic Myelogenous Leukemia cell line). In each cell line, we found several thousand instances of TEs donating coding sequences to human genes. We compared the transcriptome assembly of the RNA sequencing (RNA-Seq) reads with and without the aid of a reference transcriptome and found that the percentage of genes that incorporate TEs in their coding sequences is significantly greater than that obtained from the reference transcriptome assemblies using Refseq and Gencode gene models. We also used histone modifications chromatin immunoprecipitation sequencing (ChIP-Seq) data, Cap Analysis of Gene Expression (CAGE) data and DNAseI Hypersensitivity Site (DHS) data to demonstrate the epigenetic regulation of the TE derived coding sequences. Our results suggest that TEs form a significantly higher percentage of coding sequences than represented in gene annotation databases and these TE derived sequences are epigenetically regulated in accordance with their expression in the two cell types.
Highlights
A substantial fraction of the eukaryotic genome is comprised of transposable elements (TEs)
We found several thousand instances of TEs donating coding sequences to human genes and that TE exonization is significantly greater in the reference guided transcriptome assembly (Refseq [17] and Gencode [18]) than an assembly without the aid of a reference transcriptome
We co-located TEannotations with RNA-seq data resulting from each assembly process and discovered that the fraction of TE-derived transcripts and exons is several folds higher in non-reference guided assembly. We further evaluated these data for functional signatures such as epigenetic histone modifications present at promoters and exons, cap analysis of gene expression (CAGE) data which identifies transcript start sites (TSS), and DNAseI hypersensitive sites (DHSs) which locate actively transcribing regions as characterized by open chromatin
Summary
A substantial fraction of the eukaryotic genome is comprised of transposable elements (TEs). We have demonstrated that TEs donate thousands of unique enhancers that are modified by epigenetic histone modifications and are functionally relevant in driving cell type specific gene expression [14,15]. These studied provided the motivation to explore the global contribution of TE derived gene features in various human cell types and their potential role in gene regulation. The availability of RNA-sequencing (RNA-Seq) and epigenetic data from various human cell lines in the Encyclopedia of DNA Elements (ENCODE) project provides an unprecedented survey of the landscape of transcription genome-wide and, in a limited way, catalogues. Integration of histone modifications chromatin immunoprecipitation sequencing (ChIP-Seq) data, cap analysis of gene expression (CAGE) data and DNAseI hypersensitivity site (DHS) data allowed us to postulate that TEs contribute a substantial fraction of human coding sequences that are epigenetically regulated in accordance with the gene expression in the two cell types
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