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Title: Investigating the activity of L1 chimeric transcripts in human cancer
Author: Xu, Hang
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2016
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Transposable elements (TEs) are repetitive sequences that occupy 45% to 65% of the human genome. TEs can transfer themselves to different locations in a host genome and they have had a considerable impact on the structural and functional evolution of genomes and transcriptomes. TE mobilisation ac­tivity can have deleterious consequences and de novo insertions have been implicated in genetic disorders, and acquired diseases such as cancer. A vari­ety of mechanisms have evolved to prevent TE mobilisation in somatic cells spanning from epigenetic mechanisms that prevent transcription from TE pro­moters to the removal of TE RNAs. Activation of TE promoters also has con­sequences that are independent of mobilisation and has been reported to be responsible for increasing transcript diversity and rewiring of gene regulatory networks. A large portion of human RNA transcripts initiate within TEs with resulting changes in expression of surrounding protein-coding genes. A typ­ical example is the long interspersed nuclear element (LINE-1 or LI) family of TEs. Aberrant transcription from LI promoters can result in LI chimeric transcripts (LCTs) which contain part of LI coupled to a unique genomic se­quence. Recent evidence has suggested a causal link between certain LCTs and tumour progression, indicating their potential role in the development of cancer. The advances in high-throughput sequencing technologies provide us the opportunity to investigate the activity of LCTs on a genome-wide scale. How­ever, one of the difficulties in genome-wide LCTs study is the lack of bioinformatic tools for repetitive elements involving chimeric transcript detection. Multiple computational tools have been produced to identify chimeric tran­scripts, however, most of them discard sequences that contain TEs because of their repetitive nature. The evidence that the activity of TEs may play a role in the control of gene networks encourages the development of new approaches to look into the transcriptome datasets. Establishing a relationship between expression of a given TE and expression of an adjacent or nearby gene may give a new insight in the study of TEs. In this study, I developed a novel computational tool - TECDetec (TE Chimeric Transcripts Detector) - which implements a strategy specialised for identifying and mapping chimeric transcripts associated with TEs, using tran­scriptome profiling obtained by paired-end RNA-Seq. The activity of LCTs was then studied using TECDetec in colorectal cancer patients and cell lines as well as in breast cancer cell lines. 22 LCTs which may relate to the tumour progression in CRC were highlighted. The enrichment of LCTs in nucleus but not in cytoplasm was observed, which suggested that the activity of LCTs in the human genome may be underestimated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available