title: Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration.
abstract: 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.
authors: Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.|Physiological Genomics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors: Vidya
authors: V
authors: Ramesh
authors: Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.|Physiological Genomics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors: Efil
authors: E
authors: Bayam
authors: Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-University, 82152 Munich, Germany.
authors: Filippo M
authors: FM
authors: Cernilogar
authors: Department of Functional and Structural Biology, University of Insubria, 21052 Busto Arsizio, Italy.
authors: Ian M
authors: IM
authors: Bonapace
authors: Department of Neuropathology, Regensburg University Hospital, 93053 Regensburg, Germany.
authors: Markus
authors: M
authors: Schulze
authors: Department of Neuropathology, Regensburg University Hospital, 93053 Regensburg, Germany.
authors: Markus J
authors: MJ
authors: Riemenschneider
authors: Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-University, 82152 Munich, Germany.|Munich Center for Integrated Protein Science (CiPS), 81377 Munich, Germany.
authors: Gunnar
authors: G
authors: Schotta
authors: Institute for Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.|Physiological Genomics, Helmholtz Center Munich, 85764 Neuherberg, Germany.|SyNergy, Excellence Cluster Systems Neurology, University of Munich, 81377 Munich, Germany.
authors: Magdalena
authors: M
authors: Götz
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002470:Cell Survival / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology / Q000503:physiopathology*; D019175:DNA Methylation; D017353:Gene Deletion; D007426:Genes, Intracisternal A-Particle / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology* / Q000821:virology; D055495:Neurogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D014775:Virus Activation / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D009687:Nuclear Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse
keywords: 5hmC; IAP; Tet; neural stem cells; neuronal differentiation