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

138 Citations (Scopus)

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

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Embryonic Stem Cells
Stem cells
Embryonic Development
Embryoid Bodies
Enzymes
Gene expression
Cell Differentiation
5-Methylcytosine
Deregulation
Teratoma
Gene Expression Regulation
Knockout Mice
Embryonic Structures
Genes
Gene Expression
Defects
5-hydroxymethylcytosine
DNA

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Dawlaty, M. M., Breiling, A., Le, T., Barrasa, M. I., Raddatz, G., Gao, Q., ... 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

Loss of tet enzymes compromises proper differentiation of embryonic stem cells. / Dawlaty, Meelad M.; Breiling, Achim; Le, Thuc; Barrasa, M. Inmaculada; Raddatz, Günter; Gao, Qing; Powell, Benjamin E.; Cheng, Albert W.; Faull, Kym F.; Lyko, Frank; Jaenisch, Rudolf.

In: Developmental Cell, Vol. 29, No. 1, 14.04.2014, p. 102-111.

Research output: Contribution to journalArticle

Dawlaty, MM, Breiling, A, Le, T, Barrasa, MI, Raddatz, G, Gao, Q, Powell, BE, Cheng, AW, Faull, KF, Lyko, F & Jaenisch, R 2014, 'Loss of tet enzymes compromises proper differentiation of embryonic stem cells', Developmental Cell, vol. 29, no. 1, pp. 102-111. https://doi.org/10.1016/j.devcel.2014.03.003
Dawlaty, Meelad M. ; Breiling, Achim ; Le, Thuc ; Barrasa, M. Inmaculada ; Raddatz, Günter ; Gao, Qing ; Powell, Benjamin E. ; Cheng, Albert W. ; Faull, Kym F. ; Lyko, Frank ; Jaenisch, Rudolf. / Loss of tet enzymes compromises proper differentiation of embryonic stem cells. In: Developmental Cell. 2014 ; Vol. 29, No. 1. pp. 102-111.
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