Transient Accumulation of 5-Carboxylcytosine Indicates Involvement of Active Demethylation in Lineage Specification of Neural Stem Cells

被引：66

作者：

Wheldon, Lee M. ^{[1
]}

Abakir, Abdulkadir ^{[2
]}

Ferjentsik, Zoltan ^{[3
]}

Dudnakova, Tatiana ^{[4
]}

Strohbuecker, Stephanie ^{[2
]}

Christie, Denise ^{[3
]}

Dai, Nan ^{[5
]}

Guan, Shengxi ^{[5
]}

Foster, Jeremy M. ^{[5
]}

Correa, Ivan R., Jr. ^{[5
]}

Loose, Matthew ^{[3
]}

Dixon, James E. ^{[2
]}

Sottile, Virginie ^{[2
]}

Johnson, Andrew D. ^{[3
]}

Ruzov, Alexey ^{[2
]}

机构：

[1] Univ Nottingham, Ctr Biomol Sci, Nottingham NG7 2RD, England

[2] Univ Nottingham, Ctr Biomol Sci, Sch Med, Div Canc & Stem Cells, Nottingham NG7 2RD, England

[3] Univ Nottingham, Sch Life Sci, Nottingham NG7 2RD, England

[4] Univ Edinburgh, Sch Biol Sci, Edinburgh EH9 3JR, Midlothian, Scotland

[5] New England Biolabs Inc, Ipswich, MA 01938 USA

来源：

CELL REPORTS | 2014年 / 7卷 / 05期

基金：

英国生物技术与生命科学研究理事会;

关键词：

THYMINE DNA GLYCOSYLASE; 5-METHYLCYTOSINE OXIDATION; MAMMALIAN DEVELOPMENT; 5-HYDROXYMETHYLCYTOSINE; 5-FORMYLCYTOSINE; TET1; DYNAMICS; EXCISION; REVEALS; MEMORY;

D O I：

10.1016/j.celrep.2014.05.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

5-Methylcytosine (5mC) is an epigenetic modification involved in regulation of gene activity during differentiation. Tet dioxygenases oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised from DNA by thymine-DNA glycosylase (TDG) followed by regeneration of unmodified cytosine via the base excision repair pathway. Despite evidence that this mechanism is operative in embryonic stem cells, the role of TDG-dependent demethylation in differentiation and development is currently unclear. Here, we demonstrate that widespread oxidation of 5hmC to 5caC occurs in postimplantation mouse embryos. We show that 5fC and 5caC are transiently accumulated during lineage specification of neural stem cells (NSCs) in culture and in vivo. Moreover, 5caC is enriched at the cell-type-specific promoters during differentiation of NSCs, and TDG knockdown leads to increased 5fC/5caC levels in differentiating NSCs. Our data suggest that active demethylation contributes to epigenetic reprogramming determining lineage specification in embryonic brain.

引用

页码：1353 / 1361

页数：9

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