Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development

Meelad M. Dawlaty; Kibibi Ganz; Benjamin E. Powell; Yueh Chiang Hu; Styliani Markoulaki; Albert W. Cheng; Qing Gao; Jongpil Kim; Sang Woon Choi; David C. Page; Rudolf Jaenisch

doi:10.1016/j.stem.2011.07.010

Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development

Meelad M. Dawlaty, Kibibi Ganz, Benjamin E. Powell, Yueh Chiang Hu, Styliani Markoulaki, Albert W. Cheng, Qing Gao, Jongpil Kim, Sang Woon Choi, David C. Page, Rudolf Jaenisch^*

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

429 Scopus citations

Abstract

The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitro but its precise function in development is not well defined. To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice. Tet1 ^-/- ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development.

Original language	English (US)
Pages (from-to)	166-175
Number of pages	10
Journal	Cell stem cell
Volume	9
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2011.07.010
State	Published - Aug 5 2011

Funding

We thank Ruth Flannery for help with animal husbandry, Dongdong Fu for help with histology, J. Kwon and J. Love from Whitehead Genome Technology Core for help with microarray, and F. Soldner, G. Welstead, J. Staerk, K. Saha, B. Carey, and L. Medeiros for helpful discussions and critical reading of the manuscript. We are grateful to Dr. R. Bronson for analyzing histology slides and discussion on teratomas and Dr. M. Gehring for help with dot blots. M.M.D is a Damon Runyon Fellow. B.E.P is supported by a Ph.D. fellowship from the Boehringer Ingelheim Fonds. A.W.C. is supported by a Croucher scholarship. D.C.P is an HHMI investigator. R.J. is funded by NIH grants 5-RO1-HDO45022, 5-R37-CA084198, and 5-RO1-CA087869. R.J. is an adviser to Stemgent and cofounder of Fate Therapeutics.

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2011.07.010

Cite this

@article{60bfaf7c16b645cd9dafcf4d958fe641,

title = "Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development",

abstract = "The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitro but its precise function in development is not well defined. To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice. Tet1 -/- ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development.",

author = "Dawlaty, {Meelad M.} and Kibibi Ganz and Powell, {Benjamin E.} and Hu, {Yueh Chiang} and Styliani Markoulaki and Cheng, {Albert W.} and Qing Gao and Jongpil Kim and Choi, {Sang Woon} and Page, {David C.} and Rudolf Jaenisch",

note = "Funding Information: We thank Ruth Flannery for help with animal husbandry, Dongdong Fu for help with histology, J. Kwon and J. Love from Whitehead Genome Technology Core for help with microarray, and F. Soldner, G. Welstead, J. Staerk, K. Saha, B. Carey, and L. Medeiros for helpful discussions and critical reading of the manuscript. We are grateful to Dr. R. Bronson for analyzing histology slides and discussion on teratomas and Dr. M. Gehring for help with dot blots. M.M.D is a Damon Runyon Fellow. B.E.P is supported by a Ph.D. fellowship from the Boehringer Ingelheim Fonds. A.W.C. is supported by a Croucher scholarship. D.C.P is an HHMI investigator. R.J. is funded by NIH grants 5-RO1-HDO45022, 5-R37-CA084198, and 5-RO1-CA087869. R.J. is an adviser to Stemgent and cofounder of Fate Therapeutics. ",

year = "2011",

month = aug,

day = "5",

doi = "10.1016/j.stem.2011.07.010",

language = "English (US)",

volume = "9",

pages = "166--175",

journal = "Cell stem cell",

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T1 - Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development

AU - Dawlaty, Meelad M.

AU - Ganz, Kibibi

AU - Powell, Benjamin E.

AU - Hu, Yueh Chiang

AU - Markoulaki, Styliani

AU - Cheng, Albert W.

AU - Gao, Qing

AU - Kim, Jongpil

AU - Choi, Sang Woon

AU - Page, David C.

AU - Jaenisch, Rudolf

N1 - Funding Information: We thank Ruth Flannery for help with animal husbandry, Dongdong Fu for help with histology, J. Kwon and J. Love from Whitehead Genome Technology Core for help with microarray, and F. Soldner, G. Welstead, J. Staerk, K. Saha, B. Carey, and L. Medeiros for helpful discussions and critical reading of the manuscript. We are grateful to Dr. R. Bronson for analyzing histology slides and discussion on teratomas and Dr. M. Gehring for help with dot blots. M.M.D is a Damon Runyon Fellow. B.E.P is supported by a Ph.D. fellowship from the Boehringer Ingelheim Fonds. A.W.C. is supported by a Croucher scholarship. D.C.P is an HHMI investigator. R.J. is funded by NIH grants 5-RO1-HDO45022, 5-R37-CA084198, and 5-RO1-CA087869. R.J. is an adviser to Stemgent and cofounder of Fate Therapeutics.

PY - 2011/8/5

Y1 - 2011/8/5

N2 - The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitro but its precise function in development is not well defined. To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice. Tet1 -/- ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development.

AB - The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitro but its precise function in development is not well defined. To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice. Tet1 -/- ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development.

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DO - 10.1016/j.stem.2011.07.010

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SN - 1934-5909

VL - 9

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EP - 175

JO - Cell stem cell

JF - Cell stem cell

IS - 2

ER -

Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development

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