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ORCID

https://orcid.org/0000-0001-6571-7027

Date of Award

Summer 8-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Transposable elements (TEs) constitute a large portion of mammalian genomes, including almost half of the human genome. Yet, TEs have been largely ignored from many genomic studies. The reasons for the lack of focus on TEs in most genomic studies are twofold. Firstly TEs were thought to be ‘junk’ DNA originating from ‘selfish’ elements that do not provide any benefit to the cell. Secondly, algorithms for the alignment of next-generation sequencing reads often discard non-uniquely mapping reads that mostly enrich for repetitive sequences such as TEs. However, over the past decade, several studies have shown that TEs harbor transcription factor (TF) binding sites for certain TFs. Although these studies have changed the ‘junk’ paradigm of TE-research, the functional role of the vast number of TEs in our genome and their contribution to genetic pathways still remains to be understood. The aim of this thesis is to understand the regulatory potential of mammalian transposable elements (TEs).

A systems-level approach was taken to understand the impact and contribution of TEs to mammalian transcriptional regulatory networks. Three questions are addressed in this thesis. First, using data for twenty-six transcription factors (TFs) in various human and mouse cell types, the extent to which TEs contribute binding sites for TFs was determined. This finding showed that 2-40% of TFs’ binding sites are derived from TEs, and this percentage varies by TF and by the cell type. Second, the presence of cis-regulatory modules in TEs was investigated. A cis-regulatory module of binding sites for pluripotency TFs in mouse embryonic stem (ES) cells was identified in mouse-specific TE subfamilies. TEs from these subfamilies were capable of enhancing gene expression and are associated with genes that exhibit mouse-ES specific expression patterns. Finally, the evolution of the regulatory potential in TEs was investigated to understand when and how TEs acquire the ability to regulate gene expression. Towards this, a computational and experimental framework to study the evolution of the regulatory potential in TEs is described and outlined, with preliminary results. Together, the three questions addressed in this thesis aims to comprehensively understand the regulatory potential of TEs. With the knowledge of the regulatory potential encoded in TE subfamilies, the effect of TEs on transcriptional regulatory networks can be deciphered to gain a better understanding of the various gene expression programs or phenotypes that they can impact.

Language

English (en)

Chair and Committee

Ting Wang

Committee Members

Gary D. Stormo, Douglas Chalker, Barak A. Cohen, Justin C. Fay, James B. Skeath

Comments

Permanent URL: https://doi.org/doi:10.7936/K790224D

Available for download on Saturday, August 15, 2116

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