Ten-eleven translocation 1 mediated-DNA hydroxymethylation is required for myelination and remyelination in the mouse brain

Ming Zhang, Jian Wang, Kaixiang Zhang, Guozhen Lu, Yuming Liu, Keke Ren, Wenting Wang, Dazhuan Xin, Lingli Xu, Honghui Mao, Junlin Xing, Xingchun Gao, Weilin Jin, Kalen Berry, Katsuhiko Mikoshiba, Shengxi Wu (), Q. Richard Lu () and Xianghui Zhao ()
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Ming Zhang: Fourth Military Medical University
Jian Wang: Fourth Military Medical University
Kaixiang Zhang: Fourth Military Medical University
Guozhen Lu: Fourth Military Medical University
Yuming Liu: Fourth Military Medical University
Keke Ren: Fourth Military Medical University
Wenting Wang: Fourth Military Medical University
Dazhuan Xin: Cincinnati Children’s Hospital Medical Center
Lingli Xu: Children’s Hospital of Fudan University
Honghui Mao: Fourth Military Medical University
Junlin Xing: Fourth Military Medical University
Xingchun Gao: Xi’an Medical University
Weilin Jin: The First Hospital of Lanzhou University
Kalen Berry: Cincinnati Children’s Hospital Medical Center
Katsuhiko Mikoshiba: Toho University
Shengxi Wu: Fourth Military Medical University
Q. Richard Lu: Cincinnati Children’s Hospital Medical Center
Xianghui Zhao: Fourth Military Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: Abstract Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and 5-hydroxymethylcytosine (5hmC) profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2, impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.

Date: 2021
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DOI: 10.1038/s41467-021-25353-5

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