TY  - JOUR
AU  - Ebert, Blake C
AU  - MacArthur, Ian C
AU  - Ketchum, Harmony C
AU  - Musheev, Michael
AU  - Niehrs, Christof
AU  - Suzuki, Masako
AU  - Dawlaty, Meelad M
TI  - Establishment of neuronal and glial competence of neural stem cells requires distinct enzymatic activities of TET enzymes.
JO  - Stem cell reports
VL  - nn
SN  - 2213-6711
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - DKFZ-2025-01612
SP  - nn
PY  - 2025
N1  - DKFZ-ZMBH Alliance / epub
AB  - 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.
KW  - 5caC (Other)
KW  - 5fC (Other)
KW  - 5hmC (Other)
KW  - DNA demethylation (Other)
KW  - Neural stem cells (Other)
KW  - TET enzymes (Other)
KW  - glial (Other)
KW  - neurons (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40749667
DO  - DOI:10.1016/j.stemcr.2025.102595
UR  - https://inrepo02.dkfz.de/record/303362
ER  -