Functionally distinct roles for TET-oxidized 5-methylcytosine bases in somatic reprogramming to pluripotency.
5-Methylcytosine
/ metabolism
Animals
Cellular Reprogramming
DNA-Binding Proteins
/ genetics
Dioxygenases
Embryo, Mammalian
/ cytology
Enhancer Elements, Genetic
Epigenesis, Genetic
Fibroblasts
/ cytology
HEK293 Cells
Humans
Mice
Mice, Knockout
Mutation
NIH 3T3 Cells
Proto-Oncogene Proteins
/ genetics
5-carboxycytosine
5-formylcytosine
5-hydroxymethylcytosine
5caC
5fC
5hmC
DNA demethylation
TET
bACE-seq
epigenetics
iPSCs
induced pluripotent stem cells
reprogramming
ten-eleven translocation
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 02 2021
18 02 2021
Historique:
received:
21
05
2020
revised:
01
10
2020
accepted:
25
11
2020
pubmed:
23
12
2020
medline:
3
3
2021
entrez:
22
12
2020
Statut:
ppublish
Résumé
Active DNA demethylation via ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming in cell state transitions. TET enzymes catalyze up to three successive oxidations of 5-methylcytosine (5mC), generating 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), or 5-carboxycytosine (5caC). Although these bases are known to contribute to distinct demethylation pathways, the lack of tools to uncouple these sequential oxidative events has constrained our mechanistic understanding of the role of TETs in chromatin reprogramming. Here, we describe the first application of biochemically engineered TET mutants that unlink 5mC oxidation steps, examining their effects on somatic cell reprogramming. We show that only TET enzymes proficient for oxidation to 5fC/5caC can rescue the reprogramming potential of Tet2-deficient mouse embryonic fibroblasts. This effect correlated with rapid DNA demethylation at reprogramming enhancers and increased chromatin accessibility later in reprogramming. These experiments demonstrate that DNA demethylation through 5fC/5caC has roles distinct from 5hmC in somatic reprogramming to pluripotency.
Identifiants
pubmed: 33352108
pii: S1097-2765(20)30887-X
doi: 10.1016/j.molcel.2020.11.045
pmc: PMC7897302
mid: NIHMS1658372
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Proto-Oncogene Proteins
0
5-Methylcytosine
6R795CQT4H
Dioxygenases
EC 1.13.11.-
Tet2 protein, mouse
EC 1.13.11.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
859-869.e8Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM127408
Pays : United States
Organisme : NICHD NIH HHS
ID : F31 HD098764
Pays : United States
Organisme : NICHD NIH HHS
ID : F32 HD101230
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008216
Pays : United States
Organisme : NIGMS NIH HHS
ID : R37 GM051279
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM118501
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG010646
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM051279
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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