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

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

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.

Originalsprog	Engelsk
Tidsskrift	Nature Cell Biology
Vol/bind	25
Sider (fra-til)	481-492
ISSN	1465-7392
DOI	https://doi.org/10.1038/s41556-022-01075-8
Status	Udgivet - 2023

Bibliografisk 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).

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© 2023, The Author(s).

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