PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling

Slim Mzoughi; Jingxian Zhang; Delphine Hequet; Shun Xie Teo; Haitong Fang; Qiao Rui Xing; Marco Bezzi; Michelle Kay Yi Seah; Sheena L.M. Ong; Eun Myoung Shin; Heike Wollmann; Esther S.M. Wong; Muthafar Al-Haddawi; Colin L. Stewart; Vinay Tergaonkar; Yuin Han Loh; N. Ray Dunn; Daniel M. Messerschmidt; Ernesto Guccione

doi:10.1038/ng.3922

PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling

Slim Mzoughi, Jingxian Zhang, Delphine Hequet, Shun Xie Teo, Haitong Fang, Qiao Rui Xing, Marco Bezzi, Michelle Kay Yi Seah, Sheena L.M. Ong, Eun Myoung Shin, Heike Wollmann, Esther S.M. Wong, Muthafar Al-Haddawi, Colin L. Stewart, Vinay Tergaonkar, Yuin Han Loh, N. Ray Dunn, Daniel M. Messerschmidt, Ernesto Guccione

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42 Scopus citations

Abstract

The transcriptional network acting downstream of LIF, WNT and MAPK-ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK-ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR-Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency.

Original language	English
Pages (from-to)	1354-1363
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	9
DOIs	https://doi.org/10.1038/ng.3922
State	Published - 1 Sep 2017

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Mzoughi, S., Zhang, J., Hequet, D., Teo, S. X., Fang, H., Xing, Q. R., Bezzi, M., Seah, M. K. Y., Ong, S. L. M., Shin, E. M., Wollmann, H., Wong, E. S. M., Al-Haddawi, M., Stewart, C. L., Tergaonkar, V., Loh, Y. H., Dunn, N. R., Messerschmidt, D. M., & Guccione, E. (2017). PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling. Nature Genetics, 49(9), 1354-1363. https://doi.org/10.1038/ng.3922

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title = "PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling",

abstract = "The transcriptional network acting downstream of LIF, WNT and MAPK-ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK-ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR-Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency.",

author = "Slim Mzoughi and Jingxian Zhang and Delphine Hequet and Teo, {Shun Xie} and Haitong Fang and Xing, {Qiao Rui} and Marco Bezzi and Seah, {Michelle Kay Yi} and Ong, {Sheena L.M.} and Shin, {Eun Myoung} and Heike Wollmann and Wong, {Esther S.M.} and Muthafar Al-Haddawi and Stewart, {Colin L.} and Vinay Tergaonkar and Loh, {Yuin Han} and Dunn, {N. Ray} and Messerschmidt, {Daniel M.} and Ernesto Guccione",

year = "2017",

month = sep,

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doi = "10.1038/ng.3922",

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Mzoughi, S, Zhang, J, Hequet, D, Teo, SX, Fang, H, Xing, QR, Bezzi, M, Seah, MKY, Ong, SLM, Shin, EM, Wollmann, H, Wong, ESM, Al-Haddawi, M, Stewart, CL, Tergaonkar, V, Loh, YH, Dunn, NR, Messerschmidt, DM & Guccione, E 2017, 'PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling', Nature Genetics, vol. 49, no. 9, pp. 1354-1363. https://doi.org/10.1038/ng.3922

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T1 - PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling

AU - Mzoughi, Slim

AU - Zhang, Jingxian

AU - Hequet, Delphine

AU - Teo, Shun Xie

AU - Fang, Haitong

AU - Xing, Qiao Rui

AU - Bezzi, Marco

AU - Seah, Michelle Kay Yi

AU - Ong, Sheena L.M.

AU - Shin, Eun Myoung

AU - Wollmann, Heike

AU - Wong, Esther S.M.

AU - Al-Haddawi, Muthafar

AU - Stewart, Colin L.

AU - Tergaonkar, Vinay

AU - Loh, Yuin Han

AU - Dunn, N. Ray

AU - Messerschmidt, Daniel M.

AU - Guccione, Ernesto

PY - 2017/9/1

Y1 - 2017/9/1

N2 - The transcriptional network acting downstream of LIF, WNT and MAPK-ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK-ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR-Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency.

AB - The transcriptional network acting downstream of LIF, WNT and MAPK-ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK-ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR-Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency.

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U2 - 10.1038/ng.3922

DO - 10.1038/ng.3922

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AN - SCOPUS:85028703583

SN - 1061-4036

VL - 49

SP - 1354

EP - 1363

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling

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