Role of telomere binding protein TRF2 in neural differentiation of human embryonic stem cells
File(s)
Thesis submitted October 2013 - Resubmitted with corrections February 2014
Author(s)
Ovando Roche, Patrick
Type
Thesis
Abstract
Telomere repeat binding factor 2 (TRF2) is reported to be a key component of shelterin, a multi-protein complex that binds telomeric deoxyribonucleic acid (DNA) to protect chromosome ends and maintain genome stability. However, in recent years, TRF2 has been found to also bind non-telomeric regions and to act as a protein hub, interacting with a wide range of non-telomeric proteins and thus raising the possibility that it may serve functions independent of telomere maintenance. Despite the importance of TRF2, there is little information about how TRF2 is expressed during development and whether it could have an extratelomeric role in this process. Human embryonic stem cells (hESCs) derived from pre-implantation embryos are able to differentiate into most, if not all, tissues of the adult body, thereby provide a good cell model to tackle the problem. Given the abundance of TRF2 in the human brain and its potential for extratelomeric roles, this study focused on neural differentiation. TRF2 protein levels were found dramatically increased upon differentiation of hESCs to neural progenitor cells (NPCs) and these high levels, similarly to what is observed in vivo, were specific to the neural lineage. Gain and loss of function approaches revealed that exogenous expression of TRF2 in hESCs induced neural differentiation while, in contrast, TRF2 knockdown in NPCs drastically hindered their ability to terminally differentiate into neurons and glia. This enhancing neural function of TRF2 is achieved through the ability of TRF2 to inhibit the proteasomal degradation of REST4, an alternative splice variant of RE1-Silencing Transcription factor (REST), which alleviates REST repression over neural genes, hence consolidating neural progenitor identity and potency. This study identifies TRF2 as a novel component of neural differentiation, suggesting its importance in central nervous system development as well as in neurological disorders.
Version
Open Access
Date Issued
2013-10
Date Awarded
2014-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Cui, Wei
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
Genesis Research Trust
Grant Number
BB/D52667X/1
Publisher Department
Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)