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

Journal: 
Cell Stem Cell
Publication Year: 
2013
Authors: 
John J Vincent , Yun Huang , Pao-Yang Chen , Suhua Feng , Joseph H Calvopina , Kevin Nee , Serena A Lee , Thuc Le , Alexander J Yoon , Kym Faull , Guoping Fan , Anjana Rao , Steven E Jacobsen , Matteo Pellegrini , Amander T Clark
Public Summary: 
Scientific Abstract: 
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.

© 2013 California Institute for Regenerative Medicine