Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration.
Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration.
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DOI：
10.1101/gad.284992.116
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发表时间：
2016-10-01
影响因子：
10.5
通讯作者：
Götz M
中科院分区：
文献类型：
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作者：
Ramesh V;Bayam E;Cernilogar FM;Bonapace IM;Schulze M;Riemenschneider MJ;Schotta G;Götz M
Ramesh等表明，发育中的大脑皮层中Uhrf 1的条件性缺失导致整体DNA低甲基化，并强烈激活内源性逆转录病毒元件的脑池内A颗粒（IAP）家族。病毒蛋白的高负荷和其他转录失调最终导致出生后神经退行性变。为了了解早期表观遗传机制是否指导神经干细胞（NSC）及其后代的长期行为，我们检查了Uhrf 1（泛素样PHD环指-1;也称为Np 95），因为它在发育中的大脑的NSC中高度表达，并在分化后迅速下调。在发育中的大脑皮层中，Uhrf 1的条件性缺失导致相当正常的增殖和神经发生，但严重的生后神经退行性变。在发育过程中，Uhrf 1的缺失导致整体DNA低甲基化，伴随着内源性逆转录病毒元件的脑池内A颗粒（IAP）家族的强烈激活，伴随着5-羟甲基胞嘧啶的增加。下调泰特酶可挽救Uhrf 1条件性敲除（cKO）细胞中的IAP激活，表明Uhrf 1和泰特对IAP调节存在拮抗性相互作用。由于IAP上调持续到Uhrf 1 cKO小鼠的出生后阶段，我们的数据显示缺乏手段来抑制IAP在分化的神经元，通常从来没有表达Uhrf 1。病毒蛋白的高负荷和其他转录失调最终导致出生后神经退行性变。总之，这些数据表明，早期发育的NSC因子可以对神经元分化和存活产生长期影响。此外，他们强调了DNA甲基化的广泛变化对某些类别的逆转录病毒元件的影响是多么具体。
Ramesh et al. show that conditional deletion of Uhrf1 in the developing cerebral cortex resulted in global DNA hypomethylation with a strong activation of the intracisternal A particle (IAP) family of endogenous retroviral elements. The high load of viral proteins and other transcriptional deregulation ultimately lead to postnatal neurodegeneration. 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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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
Feng, Jian;Zhou, Yu;Campbell, Susan L.;Le, Thuc;Li, En;Sweatt, J. David;Silva, Alcino J.;Fan, Guoping
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DOI：
10.1124/jpet.112.192138
发表时间：
2012-09-01
影响因子：
3.5
作者：
Johri, Ashu;Beal, M. Flint
通讯作者：
Beal, M. Flint
影响因子：
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