TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice.
TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice.
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DOI：
10.1038/s41467-021-23735-3
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发表时间：
2021-06-07
影响因子：
16.6
通讯作者：
Casaccia P
中科院分区：
文献类型：
--
作者：
Moyon S;Frawley R;Marechal D;Huang D;Marshall-Phelps KLH;Kegel L;Bøstrand SMK;Sadowski B;Jiang YH;Lyons DA;Möbius W;Casaccia P
成人中枢神经系统髓磷脂修复的调控机制尚不清楚。在这里，我们发现由TET酶TET1催化的DNA羟甲基化是年轻成年小鼠髓磷脂修复的必要条件，而在老年小鼠中则存在缺陷。组成性和诱导性少突胶质细胞谱系特异性消融Tet1（但不是Tet2），概括了脱髓鞘病变修复中与年龄相关的下降。DNA羟甲基化和转录组学分析发现tet1靶点在成人少突胶质细胞中作为调节神经胶质通讯的基因，包括溶质载体（Slc）基因家族。其中，我们发现Na+/K+/Cl−转运体SLC12A2的表达水平在Tet1过表达的细胞中较高，而在旧的或Tet1敲除的细胞中较低。老年小鼠和Tet1突变体也表现出髓鞘修复效率低下和轴髓鞘肿胀。斑马鱼slc12a2b突变体也表现出中枢神经系统髓鞘轴突的肿胀。我们的研究结果表明TET1是成人髓磷脂修复和轴突-髓磷脂界面调节所必需的。髓磷脂的形成受表观遗传机制的调控，并确保发育过程中和脱髓鞘后神经元的正常功能。在这里，作者表明TET1，一种DNA羟化酶，调节成年小鼠的髓磷脂修复，但随着年龄的增长而出现缺陷。
The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na+/K+/Cl− transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface. Myelin formation is regulated by epigenetic mechanisms and ensures proper neuronal function during development and after demyelination. Here, the authors show that TET1, a DNA hydroxymethylase, regulates myelin repair in adult mice, but is defective with aging.
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影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
14.9
作者：
Hashimoto H;Zhang X;Cheng X
通讯作者：
Cheng X
影响因子：
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作者：
He, Ye;Sandoval, Juan;Casaccia-Bonnefil, Patrizia
通讯作者：
Casaccia-Bonnefil, Patrizia
影响因子：
3.7
作者：
Globisch D;Münzel M;Müller M;Michalakis S;Wagner M;Koch S;Brückl T;Biel M;Carell T
通讯作者：
Carell T
影响因子：
5.5
作者：
Hamann, Steffen;Herrera-Perez, Jose J.;Alvarez-Leefmans, Francisco J.
通讯作者：
Alvarez-Leefmans, Francisco J.