TRF2-Mediated Stabilization of hREST4 Is Critical for the Differentiation and Maintenance of Neural Progenitors
Author(s)
Ovando-Roche, P
Yu, JSL
Testori, S
Ho, C
Cui, W
Type
Journal Article
Abstract
Telomere repeat binding factor 2 (TRF2) is a component of the shelterin complex that is known
to bind and protect telomeric DNA, yet the detection of TRF2 in extra-telomeric regions of chromosomes
suggests other roles for TRF2 besides telomere protection. Here, we demonstrate that
TRF2 plays a critical role in antagonizing the repressive function of neuron-restrictive silencer
factor, also known as repressor element-1 silencing transcription factor (REST), during the neural
differentiation of human embryonic stem cells (hESCs) by enhancing the expression of a truncated
REST splice isoform we term human REST4 (hREST4) due to its similarity to rodent REST4.
We show that TRF2 is specifically upregulated during hESC neural differentiation concordantly
with an increase in the expression of hREST4 and that both proteins are highly expressed in
NPCs. Overexpression of TRF2 in hESCs increases hREST4 levels and induces their neural differentiation,
whereas TRF2 knockdown in hESCs and NPCs reduces hREST4 expression, hindering
their ability to differentiate to the neural lineage. Concurrently, we show that TRF2 directly
interacts with the C-terminal of hREST4 through its TRF2 core binding motif [F/Y]xL, protecting
hREST4 from ubiquitin-mediated proteasomal degradation and consequently furthering neural
induction. Thus, the TRF2-mediated counterbalance between hREST4 and REST is vital for both
the generation and maintenance of NPCs, suggesting an important role for TRF2 in both neurogenesis
and function of the central nervous system.
to bind and protect telomeric DNA, yet the detection of TRF2 in extra-telomeric regions of chromosomes
suggests other roles for TRF2 besides telomere protection. Here, we demonstrate that
TRF2 plays a critical role in antagonizing the repressive function of neuron-restrictive silencer
factor, also known as repressor element-1 silencing transcription factor (REST), during the neural
differentiation of human embryonic stem cells (hESCs) by enhancing the expression of a truncated
REST splice isoform we term human REST4 (hREST4) due to its similarity to rodent REST4.
We show that TRF2 is specifically upregulated during hESC neural differentiation concordantly
with an increase in the expression of hREST4 and that both proteins are highly expressed in
NPCs. Overexpression of TRF2 in hESCs increases hREST4 levels and induces their neural differentiation,
whereas TRF2 knockdown in hESCs and NPCs reduces hREST4 expression, hindering
their ability to differentiate to the neural lineage. Concurrently, we show that TRF2 directly
interacts with the C-terminal of hREST4 through its TRF2 core binding motif [F/Y]xL, protecting
hREST4 from ubiquitin-mediated proteasomal degradation and consequently furthering neural
induction. Thus, the TRF2-mediated counterbalance between hREST4 and REST is vital for both
the generation and maintenance of NPCs, suggesting an important role for TRF2 in both neurogenesis
and function of the central nervous system.
Date Issued
2014-04-16
Date Acceptance
2014-03-16
Citation
Stem Cells, 2014, 32 (8), pp.2111-2122
ISSN
1549-4918
Publisher
AlphaMed Press
Start Page
2111
End Page
2122
Journal / Book Title
Stem Cells
Volume
32
Issue
8
Copyright Statement
This is the peer reviewed version of the following article: Ovando-Roche, P., Yu, J. S.L., Testori, S., Ho, C. and Cui, W. (2014), TRF2-Mediated Stabilization of hREST4 Is Critical for the Differentiation and Maintenance of Neural Progenitors. STEM CELLS, 32: 2111–2122, which has been published in final form at https://dx.doi.org/10.1002/stem.1725. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving. Permission for deposit from publisher.
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Biotechnology & Applied Microbiology
Oncology
Cell Biology
Hematology
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
CELL & TISSUE ENGINEERING
CELL BIOLOGY
HEMATOLOGY
ONCOLOGY
Telomere repeat binding factor 2
REST/REST4
Neural differentiation
Neural progenitor cells
Human embryonic stem cells
EMBRYONIC STEM-CELLS
GENE-EXPRESSION
TELOMERIC PROTEINS
TRF2
TRANSCRIPTION
REPRESSOR
REST
SENESCENCE
DAMAGE
PLURIPOTENCY
Publication Status
Published