Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells

Paulina A. Latos; Angela Goncalves; David Oxley; Hisham Mohammed; Ernest Turro; Myriam Hemberger

doi:10.1038/ncomms8776

Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells

Paulina A. Latos, Angela Goncalves, David Oxley, Hisham Mohammed, Ernest Turro, Myriam Hemberger

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

72 Scopus citations

Abstract

Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.

Original language	English (US)
Article number	7776
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8776
State	Published - Jul 24 2015
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells",

abstract = "Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.",

author = "Latos, {Paulina A.} and Angela Goncalves and David Oxley and Hisham Mohammed and Ernest Turro and Myriam Hemberger",

note = "Funding Information: We thank Sasha Mendjan for helpful comments and fruitful discussions. We are grateful to Kristina Tabbada for Illumina high-throughput sequencing, Dominika Dudzinska for help with generating sequencing libraries, to Simon Andrews and Felix Krueger for help with bioinformatic analysis, to Judith Webster for assistance with Mass Spectrometry experiments, to Wojciech Latos for technical assistance and to Professor Wolf Reik for support. This work was supported by a Next Generation Fellowship awarded to P.A.L. by the Centre for Trophoblast Research, University of Cambridge by the Biotechnology and Biological Sciences research Council (BBSRC) and by the Wellcome Trust. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

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AU - Latos, Paulina A.

AU - Goncalves, Angela

AU - Oxley, David

AU - Mohammed, Hisham

AU - Turro, Ernest

AU - Hemberger, Myriam

N1 - Funding Information: We thank Sasha Mendjan for helpful comments and fruitful discussions. We are grateful to Kristina Tabbada for Illumina high-throughput sequencing, Dominika Dudzinska for help with generating sequencing libraries, to Simon Andrews and Felix Krueger for help with bioinformatic analysis, to Judith Webster for assistance with Mass Spectrometry experiments, to Wojciech Latos for technical assistance and to Professor Wolf Reik for support. This work was supported by a Next Generation Fellowship awarded to P.A.L. by the Centre for Trophoblast Research, University of Cambridge by the Biotechnology and Biological Sciences research Council (BBSRC) and by the Wellcome Trust. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/7/24

Y1 - 2015/7/24

N2 - Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.

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Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells

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