TRF2-mediated stabilization of hREST4 is critical for the differentiation and maintenance of neural progenitors

Autor: Patrick Ovando-Roche, Wei Cui, Chloe Ho, Jason S. L. Yu, Sarah Testori
Rok vydání: 2013
Předmět:
TRF2
Neural Stem Cells
Transduction
Genetic
Telomeric Repeat Binding Protein 2
TRANSCRIPTION
In Situ Hybridization
Fluorescence
GENE-EXPRESSION
DAMAGE
Genetics
Reverse Transcriptase Polymerase Chain Reaction
REST
Neurogenesis
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
REPRESSOR
Cell Differentiation
Flow Cytometry
Immunohistochemistry
Neural stem cell
Cell biology
Up-Regulation
Molecular Medicine
Human embryonic stem cells
Neural differentiation
Stem cell
Life Sciences & Biomedicine
Neural development
Immunoblotting
Biology
PLURIPOTENCY
Cell Line
HEMATOLOGY
Cell & Tissue Engineering
Gene silencing
Humans
Neural progenitor cells
Transcription factor
Embryonic Stem Cells
Science & Technology
TELOMERIC PROTEINS
Cell Biology
ONCOLOGY
Embryonic stem cell
Telomere
Repressor Proteins
SENESCENCE
REST/REST4
Telomere repeat binding factor 2
EMBRYONIC STEM-CELLS
Developmental Biology
Zdroj: Europe PubMed Central
ISSN: 1549-4918
Popis: 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. Stem Cells 2014;32:2111–2122
Databáze: OpenAIRE
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