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100 1 _ |a Ebert, Blake C
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245 _ _ |a Establishment of neuronal and glial competence of neural stem cells requires distinct enzymatic activities of TET enzymes.
260 _ _ |a Maryland Heights, MO
|c 2025
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520 _ _ |a Ten-eleven translocation (TET1/2/3) enzymes are expressed in neural stem cells (NSCs). They iteratively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). The significance of hydroxymethylation (i.e., 5hmC) versus formylation and carboxylation (i.e., active demethylation) is undefined. We generated NSCs lacking only TET formylation and carboxylation activities (Tet-TFoCa) and compared them to NSCs lacking all three TET activities (Tet-TMut). Tet-TFoCa NSCs could differentiate into neurons but not into glial cells, while Tet-TMut NSCs could not form either cell type. Mechanistically, neuronal genes retained 5hmC at their enhancers in Tet-TFoCa NSCs and were expressed normally, consistent with the ability of these cells to form neurons. In contrast, enhancers of glial genes were hypermethylated in both Tet-TFoCa and Tet-TMut NSCs underpinning downregulation of these genes and the glial block in these cells. Our findings implicate TET-driven hydroxymethylation in establishing NSC neuronal competence and formylation and carboxylation in defining NSC glial competence.
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650 _ 7 |a 5hmC
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650 _ 7 |a DNA demethylation
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650 _ 7 |a Neural stem cells
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650 _ 7 |a TET enzymes
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650 _ 7 |a glial
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650 _ 7 |a neurons
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700 1 _ |a MacArthur, Ian C
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700 1 _ |a Ketchum, Harmony C
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700 1 _ |a Musheev, Michael
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700 1 _ |a Niehrs, Christof
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700 1 _ |a Suzuki, Masako
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700 1 _ |a Dawlaty, Meelad M
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773 _ _ |a 10.1016/j.stemcr.2025.102595
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