TET1-mediated Oligodendrocyte Homeostasis Regulates Myelination and Synaptic Functions
TET1-mediated Oligodendrocyte Homeostasis Regulates Myelination and Synaptic Functions
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TET1 介导的少突胶质细胞稳态调节髓鞘形成和突触功能
DOI：
10.1101/821496
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发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
赵湘辉
中科院分区：
文献类型：
--
作者：
赵湘辉
摘要DNA甲基化对少突胶质细胞的发育至关重要。然而，在少突胶质细胞动态平衡、髓鞘形成和再髓鞘形成过程中，受Ten-11易位(Tet)双加氧酶调控的反向过程-DNA去甲基化的作用仍然不清楚。在这里，我们确定了在少突胶质细胞前体细胞(OPC)分化过程中全基因组和特定位点的DNA羟甲基化格局的变化。Tet1消融导致发育中的脑内少突胶质细胞发育和髓鞘形成缺陷，而成人脑脱髓鞘后再髓鞘形成受损。转录和DNA羟甲基化分析揭示了TET1调节少突胶质细胞分化的表观遗传程序，并确定了一组与钙稳态相关的靶基因。Tet1缺乏的OPC表现出[Ca~(2+)]振荡减少，而钙通道的激活部分恢复了Tet1缺乏的OPC的分化缺陷。此外，由Tet1缺乏引起的少突胶质细胞内稳态失调损害了动作电位的传播和突触传递。因此，我们的结果表明，在细胞自主和非细胞自主机制中，适当的髓鞘形成和修复以及神经元生理学分别需要特定阶段的TET1介导的少突胶质细胞动态平衡的表观遗传编程。
Abstract DNA methylation is critical for oligodendrocyte development. The role of the converse process, DNA demethylation regulated by Ten-Eleven-Translocation (TET) dioxygenases, in oligodendrocyte homeostasis, myelination and remyelination however remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during oligodendrocyte progenitor cell (OPC) differentiation. Tet1 ablation results in defects in oligodendrocyte development and myelination in the developing brain, while impairing remyelination after demyelination in adult brains. Transcriptomic and DNA hydroxymethylation analyses reveal a TET1-regulated epigenetic program for oligodendrocyte differentiation and identify a set of target genes associated with Ca2+ homeostasis. Tet1-deficient OPCs exhibited reduced [Ca2+] oscillations, while activation of calcium channels partially restores the differentiation defect of Tet1-deficient OPCs. Moreover, dysregulated oligodendrocyte homeostasis caused by Tet1-deficiency impairs action potential propagation and synaptic transmission. Thus, our results suggest that stage-specific TET1-mediated epigenetic programming of oligodendrocyte homeostasis is required for proper myelination and repair as well as neuronal physiology in cell-autonomous and non-cell-autonomous mechanisms, respectively.
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影响因子：
3.8
作者：
Andy Madrid;L. Papale;Reid S. Alisch
通讯作者：
Andy Madrid;L. Papale;Reid S. Alisch
影响因子：
4.5
作者：
Hornig J;Fröb F;Vogl MR;Hermans-Borgmeyer I;Tamm ER;Wegner M
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Wegner M
影响因子：
25
作者：
Ballas, Nurit;Lioy, Daniel T.;Grunseich, Christopher;Mandel, Gail
通讯作者：
Mandel, Gail
影响因子：
2.9
作者：
Ferrer-Ferrer M;Dityatev A
通讯作者：
Dityatev A
影响因子：
11
作者：
Harripaul, R.;Vasli, N.;Vincent, J. B.
通讯作者：
Vincent, J. B.