DAZL regulates Tet1 translation in murine embryonic stem cells

Maaike Welling; Hsu-Hsin Chen; Javier Muñoz; Michael U Musheev; Lennart Kester; Jan Philipp Junker; Nikolai Mischerikow; Mandana Arbab; Ewart Kuijk; Lev Silberstein; Peter V Kharchenko; Mieke Geens; Christof Niehrs; Hilde van de Velde; Alexander van Oudenaarden; Albert Jr Heck; Niels Geijsen

doi:10.15252/embr.201540538

DAZL regulates Tet1 translation in murine embryonic stem cells

Maaike Welling, Hsu-Hsin Chen, Javier Muñoz, Michael U Musheev, Lennart Kester, Jan Philipp Junker, Nikolai Mischerikow, Mandana Arbab, Ewart Kuijk, Lev Silberstein, Peter V Kharchenko, Mieke Geens, Christof Niehrs, Hilde van de Velde, Alexander van Oudenaarden, Albert Jr Heck, Niels Geijsen

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

20 Citaten (Scopus)

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Embryonic stem cell (ESC) cultures display a heterogeneous gene expression profile, ranging from a pristine naïve pluripotent state to a primed epiblast state. Addition of inhibitors of GSK3β and MEK (so-called 2i conditions) pushes ESC cultures toward a more homogeneous naïve pluripotent state, but the molecular underpinnings of this naïve transition are not completely understood. Here, we demonstrate that DAZL, an RNA-binding protein known to play a key role in germ-cell development, marks a subpopulation of ESCs that is actively transitioning toward naïve pluripotency. Moreover, DAZL plays an essential role in the active reprogramming of cytosine methylation. We demonstrate that DAZL associates with mRNA of Tet1, a catalyst of 5-hydroxylation of methyl-cytosine, and enhances Tet1 mRNA translation. Overexpression of DAZL in heterogeneous ESC cultures results in elevated TET1 protein levels as well as increased global hydroxymethylation. Conversely, null mutation of Dazl severely stunts 2i-mediated TET1 induction and hydroxymethylation. Our results provide insight into the regulation of the acquisition of naïve pluripotency and demonstrate that DAZL enhances TET1-mediated cytosine hydroxymethylation in ESCs that are actively reprogramming to a pluripotent ground state.

Originele taal-2	Engels
Pagina's (van-tot)	791-802
Aantal pagina's	12
Tijdschrift	EMBO Reports
Volume	16
Nummer van het tijdschrift	7
DOI's	https://doi.org/10.15252/embr.201540538
Status	Gepubliceerd - jul. 2015

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Welling, M., Chen, H.-H., Muñoz, J., Musheev, M. U., Kester, L., Junker, J. P., Mischerikow, N., Arbab, M., Kuijk, E., Silberstein, L., Kharchenko, P. V., Geens, M., Niehrs, C., van de Velde, H., van Oudenaarden, A., Heck, A. J., & Geijsen, N. (2015). DAZL regulates Tet1 translation in murine embryonic stem cells. EMBO Reports, 16(7), 791-802. https://doi.org/10.15252/embr.201540538

@article{39f28298590f46f68d04678f5fdd8fc6,

title = "DAZL regulates Tet1 translation in murine embryonic stem cells",

abstract = "Embryonic stem cell (ESC) cultures display a heterogeneous gene expression profile, ranging from a pristine na{\"i}ve pluripotent state to a primed epiblast state. Addition of inhibitors of GSK3β and MEK (so-called 2i conditions) pushes ESC cultures toward a more homogeneous na{\"i}ve pluripotent state, but the molecular underpinnings of this na{\"i}ve transition are not completely understood. Here, we demonstrate that DAZL, an RNA-binding protein known to play a key role in germ-cell development, marks a subpopulation of ESCs that is actively transitioning toward na{\"i}ve pluripotency. Moreover, DAZL plays an essential role in the active reprogramming of cytosine methylation. We demonstrate that DAZL associates with mRNA of Tet1, a catalyst of 5-hydroxylation of methyl-cytosine, and enhances Tet1 mRNA translation. Overexpression of DAZL in heterogeneous ESC cultures results in elevated TET1 protein levels as well as increased global hydroxymethylation. Conversely, null mutation of Dazl severely stunts 2i-mediated TET1 induction and hydroxymethylation. Our results provide insight into the regulation of the acquisition of na{\"i}ve pluripotency and demonstrate that DAZL enhances TET1-mediated cytosine hydroxymethylation in ESCs that are actively reprogramming to a pluripotent ground state.",

author = "Maaike Welling and Hsu-Hsin Chen and Javier Mu{\~n}oz and Musheev, {Michael U} and Lennart Kester and Junker, {Jan Philipp} and Nikolai Mischerikow and Mandana Arbab and Ewart Kuijk and Lev Silberstein and Kharchenko, {Peter V} and Mieke Geens and Christof Niehrs and {van de Velde}, Hilde and {van Oudenaarden}, Alexander and Heck, {Albert Jr} and Niels Geijsen",

note = "{\textcopyright} 2015 The Authors.",

year = "2015",

month = jul,

doi = "10.15252/embr.201540538",

language = "English",

volume = "16",

pages = "791--802",

journal = "EMBO Reports",

issn = "1469-221X",

publisher = "Nature Publishing Group",

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Welling, M, Chen, H-H, Muñoz, J, Musheev, MU, Kester, L, Junker, JP, Mischerikow, N, Arbab, M, Kuijk, E, Silberstein, L, Kharchenko, PV, Geens, M, Niehrs, C, van de Velde, H, van Oudenaarden, A, Heck, AJ & Geijsen, N 2015, 'DAZL regulates Tet1 translation in murine embryonic stem cells', EMBO Reports, vol. 16, nr. 7, blz. 791-802. https://doi.org/10.15252/embr.201540538

TY - JOUR

T1 - DAZL regulates Tet1 translation in murine embryonic stem cells

AU - Welling, Maaike

AU - Chen, Hsu-Hsin

AU - Muñoz, Javier

AU - Musheev, Michael U

AU - Kester, Lennart

AU - Junker, Jan Philipp

AU - Mischerikow, Nikolai

AU - Arbab, Mandana

AU - Kuijk, Ewart

AU - Silberstein, Lev

AU - Kharchenko, Peter V

AU - Geens, Mieke

AU - Niehrs, Christof

AU - van de Velde, Hilde

AU - van Oudenaarden, Alexander

AU - Heck, Albert Jr

AU - Geijsen, Niels

PY - 2015/7

Y1 - 2015/7

N2 - Embryonic stem cell (ESC) cultures display a heterogeneous gene expression profile, ranging from a pristine naïve pluripotent state to a primed epiblast state. Addition of inhibitors of GSK3β and MEK (so-called 2i conditions) pushes ESC cultures toward a more homogeneous naïve pluripotent state, but the molecular underpinnings of this naïve transition are not completely understood. Here, we demonstrate that DAZL, an RNA-binding protein known to play a key role in germ-cell development, marks a subpopulation of ESCs that is actively transitioning toward naïve pluripotency. Moreover, DAZL plays an essential role in the active reprogramming of cytosine methylation. We demonstrate that DAZL associates with mRNA of Tet1, a catalyst of 5-hydroxylation of methyl-cytosine, and enhances Tet1 mRNA translation. Overexpression of DAZL in heterogeneous ESC cultures results in elevated TET1 protein levels as well as increased global hydroxymethylation. Conversely, null mutation of Dazl severely stunts 2i-mediated TET1 induction and hydroxymethylation. Our results provide insight into the regulation of the acquisition of naïve pluripotency and demonstrate that DAZL enhances TET1-mediated cytosine hydroxymethylation in ESCs that are actively reprogramming to a pluripotent ground state.

AB - Embryonic stem cell (ESC) cultures display a heterogeneous gene expression profile, ranging from a pristine naïve pluripotent state to a primed epiblast state. Addition of inhibitors of GSK3β and MEK (so-called 2i conditions) pushes ESC cultures toward a more homogeneous naïve pluripotent state, but the molecular underpinnings of this naïve transition are not completely understood. Here, we demonstrate that DAZL, an RNA-binding protein known to play a key role in germ-cell development, marks a subpopulation of ESCs that is actively transitioning toward naïve pluripotency. Moreover, DAZL plays an essential role in the active reprogramming of cytosine methylation. We demonstrate that DAZL associates with mRNA of Tet1, a catalyst of 5-hydroxylation of methyl-cytosine, and enhances Tet1 mRNA translation. Overexpression of DAZL in heterogeneous ESC cultures results in elevated TET1 protein levels as well as increased global hydroxymethylation. Conversely, null mutation of Dazl severely stunts 2i-mediated TET1 induction and hydroxymethylation. Our results provide insight into the regulation of the acquisition of naïve pluripotency and demonstrate that DAZL enhances TET1-mediated cytosine hydroxymethylation in ESCs that are actively reprogramming to a pluripotent ground state.

U2 - 10.15252/embr.201540538

DO - 10.15252/embr.201540538

M3 - Article

C2 - 26077710

SN - 1469-221X

VL - 16

SP - 791

EP - 802

JO - EMBO Reports

JF - EMBO Reports

IS - 7

ER -

DAZL regulates Tet1 translation in murine embryonic stem cells

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