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Ramesh, V. ; Bayam, E. ; Cernilogar, F.M.* ; Bonapace, I.M.* ; Schulze, M.* ; Riemenschneider, M.J.* ; Schotta, G.* ; Götz, M.

Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration.

Genes Dev. 30, 2199-2212 (2016)
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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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache
Veröffentlichungsjahr 2016
HGF-Berichtsjahr 2016
ISSN (print) / ISBN 0890-9369
e-ISSN 1549-5477
Zeitschrift Genes and Development
Quellenangaben Band: 30, Heft: 19, Seiten: 2199-2212 Artikelnummer: , Supplement: ,
Verlag Cold Spring Harbor Laboratory Press
Verlagsort Cold Spring Harbor
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Stem Cell Research (ISF)
POF Topic(s) 30204 - Cell Programming and Repair
Forschungsfeld(er) Stem Cell and Neuroscience
PSP-Element(e) G-500800-001
DOI 10.1101/gad.284992.116
WOS ID WOS:000386544900006
Scopus ID 84992034522
Erfassungsdatum 2016-11-02
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