Expansion of ventral foregut is linked to changes in the enhancer landscape for organ-specific differentiation

Yan Fung Wong; Yatendra Kumar; Martin Proks; Jose Alejandro Romero Herrera; Michaela Mrugala Rothová; Rita S. Monteiro; Sara Pozzi; Rachel E. Jennings; Neil A. Hanley; Wendy A. Bickmore; Joshua M. Brickman

doi:10.1038/s41556-022-01075-8

Expansion of ventral foregut is linked to changes in the enhancer landscape for organ-specific differentiation

Yan Fung Wong, Yatendra Kumar, Martin Proks, Jose Alejandro Romero Herrera, Michaela Mrugala Rothová, Rita S. Monteiro, Sara Pozzi, Rachel E. Jennings, Neil A. Hanley, Wendy A. Bickmore^*, Joshua M. Brickman^*

^*Corresponding author for this work

Medical and Dental Sciences

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

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Abstract

Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.

Original language	English
Pages (from-to)	481-492
Number of pages	12
Journal	Nature Cell Biology
Volume	25
Issue number	3
Early online date	23 Jan 2023
DOIs	https://doi.org/10.1038/s41556-022-01075-8
Publication status	Published - Mar 2023

Bibliographical note

Funding Information:
We thank P. Gadue for sharing protocols for EP expansion, H. Semb for the HUES4 WT and PDXeG clone 170-3 cell lines and K. Helin for the lentiviral vector; we thank the reNEW Genomics Platform, reNEW Flow Cytometry Platform, the reNEW Imaging Platform and the reNEW Stem Cell Culture Platform for training, technical expertise, support and the use of instruments. We also thank members of the Brickman and Bickmore labs for critical comments on this manuscript. We are grateful to A. G. Botton for critical reading of the manuscript. This work was funded by HumEn under the European Union Seventh Framework Programme FP7/2007-2013 (HEALTH-F4-2013-602889). J.M.B. was supported by Novo Nordisk Foundation (NNF21OC0070898), Danmarks Frie Forskningsfond (DFF-6110-00009) and Lundbeckfonden (R198-2015-412). W.A.B. was supported by MRC University Unit grant (MC_UU_00007/2). N.A.H. was supported by MRC (MR/000638/1 and MR/S036121/1). R.E.J. is a Diabetes UK Harry Keen Clinician Scientist fellow. J.A.R.H. was also supported by the Novo Nordisk Foundation (grant number NNF20OC0063268). R.S.M. was supported by a Lundbeckfonden post-doctoral fellowship (R303-2018-2939). The Novo Nordisk Foundation Center for Stem Cell Medicine is supported by Novo Nordisk Foundation (grant number NNF21CC0073729 and previously NNF17CC0027852).

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

Cell Biology

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Cite this

@article{50da1446536c445ebb989869a3ab69ed,

title = "Expansion of ventral foregut is linked to changes in the enhancer landscape for organ-specific differentiation",

abstract = "Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.",

author = "Wong, {Yan Fung} and Yatendra Kumar and Martin Proks and Herrera, {Jose Alejandro Romero} and Rothov{\'a}, {Michaela Mrugala} and Monteiro, {Rita S.} and Sara Pozzi and Jennings, {Rachel E.} and Hanley, {Neil A.} and Bickmore, {Wendy A.} and Brickman, {Joshua M.}",

note = "Funding Information: We thank P. Gadue for sharing protocols for EP expansion, H. Semb for the HUES4 WT and PDXeG clone 170-3 cell lines and K. Helin for the lentiviral vector; we thank the reNEW Genomics Platform, reNEW Flow Cytometry Platform, the reNEW Imaging Platform and the reNEW Stem Cell Culture Platform for training, technical expertise, support and the use of instruments. We also thank members of the Brickman and Bickmore labs for critical comments on this manuscript. We are grateful to A. G. Botton for critical reading of the manuscript. This work was funded by HumEn under the European Union Seventh Framework Programme FP7/2007-2013 (HEALTH-F4-2013-602889). J.M.B. was supported by Novo Nordisk Foundation (NNF21OC0070898), Danmarks Frie Forskningsfond (DFF-6110-00009) and Lundbeckfonden (R198-2015-412). W.A.B. was supported by MRC University Unit grant (MC_UU_00007/2). N.A.H. was supported by MRC (MR/000638/1 and MR/S036121/1). R.E.J. is a Diabetes UK Harry Keen Clinician Scientist fellow. J.A.R.H. was also supported by the Novo Nordisk Foundation (grant number NNF20OC0063268). R.S.M. was supported by a Lundbeckfonden post-doctoral fellowship (R303-2018-2939). The Novo Nordisk Foundation Center for Stem Cell Medicine is supported by Novo Nordisk Foundation (grant number NNF21CC0073729 and previously NNF17CC0027852). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = mar,

doi = "10.1038/s41556-022-01075-8",

language = "English",

volume = "25",

pages = "481--492",

journal = "Nature Cell Biology",

issn = "1465-7392",

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T1 - Expansion of ventral foregut is linked to changes in the enhancer landscape for organ-specific differentiation

AU - Wong, Yan Fung

AU - Kumar, Yatendra

AU - Proks, Martin

AU - Herrera, Jose Alejandro Romero

AU - Rothová, Michaela Mrugala

AU - Monteiro, Rita S.

AU - Pozzi, Sara

AU - Jennings, Rachel E.

AU - Hanley, Neil A.

AU - Bickmore, Wendy A.

AU - Brickman, Joshua M.

N1 - Funding Information: We thank P. Gadue for sharing protocols for EP expansion, H. Semb for the HUES4 WT and PDXeG clone 170-3 cell lines and K. Helin for the lentiviral vector; we thank the reNEW Genomics Platform, reNEW Flow Cytometry Platform, the reNEW Imaging Platform and the reNEW Stem Cell Culture Platform for training, technical expertise, support and the use of instruments. We also thank members of the Brickman and Bickmore labs for critical comments on this manuscript. We are grateful to A. G. Botton for critical reading of the manuscript. This work was funded by HumEn under the European Union Seventh Framework Programme FP7/2007-2013 (HEALTH-F4-2013-602889). J.M.B. was supported by Novo Nordisk Foundation (NNF21OC0070898), Danmarks Frie Forskningsfond (DFF-6110-00009) and Lundbeckfonden (R198-2015-412). W.A.B. was supported by MRC University Unit grant (MC_UU_00007/2). N.A.H. was supported by MRC (MR/000638/1 and MR/S036121/1). R.E.J. is a Diabetes UK Harry Keen Clinician Scientist fellow. J.A.R.H. was also supported by the Novo Nordisk Foundation (grant number NNF20OC0063268). R.S.M. was supported by a Lundbeckfonden post-doctoral fellowship (R303-2018-2939). The Novo Nordisk Foundation Center for Stem Cell Medicine is supported by Novo Nordisk Foundation (grant number NNF21CC0073729 and previously NNF17CC0027852). Publisher Copyright: © 2023, The Author(s).

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N2 - Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.

AB - Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.

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DO - 10.1038/s41556-022-01075-8

M3 - Article

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AN - SCOPUS:85146688991

SN - 1465-7392

VL - 25

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EP - 492

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 3

ER -

Expansion of ventral foregut is linked to changes in the enhancer landscape for organ-specific differentiation

Abstract

Bibliographical note

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