Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration [P5]

In order to understand if early epigenetic mechanisms instruct the long-term behaviour of neural stem cells (NSCs) and their progeny, we examined the protein Uhrf1 as it is highly expressed in NSCs of the developing brain and rapidly downregulated 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 resulted in global DNA hypomethylation with a strong activation of the IAP family of endogenous retroviral elements, accompanied by an increase in hydroxy methyl cytosine. Downregulation of Tet enzymes rescued the IAP activation in Uhrf1 cKO cells, suggesting an antagonistic interplay between Uhrf1 and Tet on IAP regulation. As IAP upregulation persists into postnatal stages in the conditional Uhrf1 KO 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 dysregulation ultimately lead to extensive postnatal neurodegeneration. Taken together, these data show that early developmental NSC factors can have long-term effects in neuronal differentiation and survival. Moreover, it highlights how specific the consequences of widespread changes in DNA methylation are for certain classes of retroviral elements. Transcriptome analysis in control vs. Uhrf1-deficient brain为探究早期表观遗传机制是否调控神经干细胞（NSCs）及其子代细胞的长期行为，我们对Uhrf1蛋白展开研究。该蛋白在发育中大脑的神经干细胞内呈高表达状态，并在细胞分化时迅速下调。在发育中的大脑皮层中条件性敲除Uhrf1，虽使细胞增殖与神经发生保持基本正常，却引发了严重的产后神经退行性变。发育阶段的Uhrf1敲除会导致全基因组DNA低甲基化，同时强烈激活内源性逆转录病毒元件的IAP家族，并伴随羟甲基胞嘧啶水平升高。Tet酶的下调可挽救Uhrf1条件性敲除细胞中的IAP激活现象，提示Uhrf1与Tet酶在IAP调控过程中存在拮抗相互作用。由于Uhrf1条件性敲除小鼠体内的IAP上调可持续至产后阶段，本研究数据表明，在正常情况下不表达Uhrf1的分化神经元中，缺乏抑制IAP的有效机制。大量病毒蛋白积累及其他转录失调事件最终引发了广泛的产后神经退行性变。综上，本研究数据证实早期发育阶段的神经干细胞因子可对神经元分化与存活产生长期影响。此外，该研究还揭示了DNA甲基化的广泛变化对特定类别逆转录病毒元件的影响具有高度特异性。本研究包含对照组与Uhrf1缺陷型大脑的转录组分析。