Genome-Wide Reprogramming in the Mouse Germ Line Entails the Base Excision Repair Pathway

被引:346
作者
Hajkova, Petra [1 ,3 ]
Jeffries, Sean J. [1 ,4 ]
Lee, Caroline [1 ]
Miller, Nigel [2 ]
Jackson, Stephen P. [1 ,5 ]
Surani, M. Azim [1 ]
机构
[1] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst Canc & Dev, Cambridge CB2 1QN, England
[2] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England
[3] MRC, Ctr Clin Sci, London W12 0NN, England
[4] Templeman Automat, Somerville, MA 02143 USA
[5] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England
基金
英国惠康基金;
关键词
DNA METHYLATION; MAMMALIAN-CELLS; PATERNAL GENOME; DEMETHYLATION; CHROMATIN; 5-HYDROXYMETHYLCYTOSINE; POLY(ADP-RIBOSYL)ATION; EMBRYOGENESIS; ARABIDOPSIS; DEMETER;
D O I
10.1126/science.1187945
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Genome-wide active DNA demethylation in primordial germ cells (PGCs), which reprograms the epigenome for totipotency, is linked to changes in nuclear architecture, loss of histone modifications, and widespread histone replacement. Here, we show that DNA demethylation in the mouse PGCs is mechanistically linked to the appearance of single-stranded DNA (ssDNA) breaks and the activation of the base excision repair (BER) pathway, as is the case in the zygote where the paternal pronucleus undergoes active DNA demethylation shortly after fertilization. Whereas BER might be triggered by deamination of a methylcytosine (5mC), cumulative evidence indicates other mechanisms in germ cells. We demonstrate that DNA repair through BER represents a core component of genome-wide DNA demethylation in vivo and provides a mechanistic link to the extensive chromatin remodeling in developing PGCs.
引用
收藏
页码:78 / 82
页数:5
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