Loss of tet enzymes compromises proper differentiation of embryonic stem cells

Meelad M. Dawlaty, Achim Breiling, Thuc Le, M. Inmaculada Barrasa, Günter Raddatz, Qing Gao, Benjamin E. Powell, Albert W. Cheng, Kym F. Faull, Frank Lyko, Rudolf Jaenisch

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and aredynamically expressed during development. Whereas loss of individual Tet enzymes or combined deficiency of Tet1/2 allows for embryogenesis, the effect of complete loss of Tet activity and 5hmC marks in development is not established. We have generated Tet1/2/3 triple-knockout (TKO) mouse embryonic stem cells (ESCs) and examined their developmental potential. Combined deficiency of all three Tets depleted 5hmC and impaired ESC differentiation, as seen in poorly differentiated TKO embryoid bodies (EBs) and teratomas. Consistent with impaired differentiation, TKO ESCs contributed poorly to chimeric embryos, a defect rescued by Tet1 reexpression, and could not support embryonic development. Global gene-expression and methylome analyses of TKO EBs revealed promoter hypermethylation and deregulation of genes implicated in embryonic development and differentiation. These findings suggest a requirement for Tet- and 5hmC-mediated DNA demethylation in proper regulation of gene expression during ESC differentiation and development.

Original languageEnglish (US)
Pages (from-to)102-111
Number of pages10
JournalDevelopmental cell
Volume29
Issue number1
DOIs
StatePublished - Apr 14 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Dawlaty, M. M., Breiling, A., Le, T., Barrasa, M. I., Raddatz, G., Gao, Q., Powell, B. E., Cheng, A. W., Faull, K. F., Lyko, F., & Jaenisch, R. (2014). Loss of tet enzymes compromises proper differentiation of embryonic stem cells. Developmental cell, 29(1), 102-111. https://doi.org/10.1016/j.devcel.2014.03.003