Stage-Specific Roles for Tet1 and Tet2 in DNA Demethylation in Primordial Germ Cells

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• 作者：John J. Vincent¹ ; ² ; ³ ; Yun Huang⁷ ; Pao-Yang Chen² ; ³ ; ⁸ ; Suhua Feng² ; ³ ; Joseph H. Calvopiñ ; a² ; ³ ; Kevin Nee² ; Serena A. Lee² ; Thuc Le⁴ ; ⁵ ; Alexander J. Yoon¹ ; ⁵ ; Kym Faull¹ ; ⁵ ; Guoping Fan¹ ; ³ ; ⁴ ; Anjana Rao⁷ ; Steven E. Jacobsen¹ ; ² ; ³ ; ⁶ ; Matteo Pellegrini¹ ; ² ; ³ ; Amander T. Clark¹ ; ² ; ³ ; ^{clarka@ucla.edu}
• 刊名：Cell Stem Cell
• 出版年：2013
• 出版时间：4 April, 2013
• 年：2013
• 卷：12
• 期：4
• 页码：470-478
• 全文大小：1116 K

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Summary

Primordial germ cells (PGCs) undergo dramatic rearrangements to their methylome during embryogenesis, including initial genome-wide DNA demethylation that establishes the germline epigenetic ground state. The role of the 5-methylcytosine (5mC) dioxygenases Tet1 and Tet2 in the initial genome-wide DNA demethylation process has not been examined directly. Using PGCs differentiated from either control or Tet2^?/?; Tet1 knockdown embryonic stem cells (ESCs), we show that in?vitro PGC (iPGC) formation and genome-wide DNA demethylation are unaffected by the absence of Tet1 and Tet2, and thus 5-hydroxymethylcytosine (5hmC). However, numerous promoters and gene bodies were hypermethylated in mutant iPGCs, which is consistent with a role for 5hmC as an intermediate in locus-specific demethylation. Altogether, our results support a revised model of PGC DNA demethylation in which the first phase of comprehensive 5mC loss does not involve 5hmC. Instead, Tet1 and Tet2 have a locus-specific role in shaping the PGC epigenome during subsequent development.