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Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration.
Genes Dev. 30, 2199-2212 (2016)
In order to understand whether early epigenetic mechanisms instruct the long-term behavior of neural stem cells (NSCs) and their progeny, we examined Uhrf1 (ubiquitin-like PHD ring finger-1; also known as Np95), as it is highly expressed in NSCs of the developing brain and rapidly down-regulated upon differentiation. Conditional deletion of Uhrf1 in the developing cerebral cortex resulted in rather normal proliferation and neurogenesis but severe postnatal neurodegeneration. During development, deletion of Uhrf1 lead to global DNA hypomethylation with a strong activation of the intracisternal A particle (IAP) family of endogenous retroviral elements, accompanied by an increase in 5-hydroxymethylcytosine. Down-regulation of Tet enzymes rescued the IAP activation in Uhrf1 conditional knockout (cKO) cells, suggesting an antagonistic interplay between Uhrf1 and Tet on IAP regulation. As IAP up-regulation persists into postnatal stages in the Uhrf1 cKO mice, our data show the lack of means to repress IAPs in differentiating neurons that normally never express Uhrf1. The high load of viral proteins and other transcriptional deregulation ultimately led to postnatal neurodegeneration. Taken together, these data show that early developmental NSC factors can have long-term effects in neuronal differentiation and survival. Moreover, they highlight how specific the consequences of widespread changes in DNA methylation are for certain classes of retroviral elements.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
5hmc ; Iap ; Neural Stem Cells ; Neuronal Differentiation ; Tet; Hemi-methylated Dna; Endogenous Retroviruses; Mammalian-cells; Protein Uhrf1; Self-renewal; Sra Domain; Dnmt1; 5-hydroxymethylcytosine; Methyltransferase; Expression
Language
Publication Year
2016
HGF-reported in Year
2016
ISSN (print) / ISBN
0890-9369
e-ISSN
1549-5477
Journal
Genes and Development
Quellenangaben
Volume: 30,
Issue: 19,
Pages: 2199-2212
Publisher
Cold Spring Harbor Laboratory Press
Publishing Place
Cold Spring Harbor
Reviewing status
Peer reviewed
Institute(s)
Institute of Stem Cell Research (ISF)
POF-Topic(s)
30204 - Cell Programming and Repair
Research field(s)
Stem Cell and Neuroscience
PSP Element(s)
G-500800-001
WOS ID
WOS:000386544900006
Scopus ID
84992034522
Erfassungsdatum
2016-11-02