Cargando…

Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming

During embryonic development cells acquire identity as they proliferate, implying that an intrinsic facet of cell fate choice requires coupling lineage decisions to cell division. How is the cell cycle regulated to promote or suppress heterogeneity and differentiation? We explore this question combi...

Descripción completa

Detalles Bibliográficos
Autores principales: Perera, Marta, Nissen, Silas Boye, Proks, Martin, Pozzi, Sara, Monteiro, Rita S, Trusina, Ala, Brickman, Joshua M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9417417/
https://www.ncbi.nlm.nih.gov/pubmed/35969041
http://dx.doi.org/10.7554/eLife.78967
_version_ 1784776710807355392
author Perera, Marta
Nissen, Silas Boye
Proks, Martin
Pozzi, Sara
Monteiro, Rita S
Trusina, Ala
Brickman, Joshua M
author_facet Perera, Marta
Nissen, Silas Boye
Proks, Martin
Pozzi, Sara
Monteiro, Rita S
Trusina, Ala
Brickman, Joshua M
author_sort Perera, Marta
collection PubMed
description During embryonic development cells acquire identity as they proliferate, implying that an intrinsic facet of cell fate choice requires coupling lineage decisions to cell division. How is the cell cycle regulated to promote or suppress heterogeneity and differentiation? We explore this question combining time lapse imaging with single-cell RNA-seq in the contexts of self-renewal, priming, and differentiation of mouse embryonic stem cells (ESCs) towards the Primitive Endoderm (PrE) lineage. Since ESCs are derived from the inner cell mass (ICM) of the mammalian blastocyst, ESCs in standard culture conditions are transcriptionally heterogeneous containing dynamically interconverting subfractions primed for either of the two ICM lineages, Epiblast and PrE. Here, we find that differential regulation of cell cycle can tip the balance between these primed populations, such that naïve ESC culture promotes Epiblast-like expansion and PrE differentiation stimulates the selective survival and proliferation of PrE-primed cells. In endoderm differentiation, this change is accompanied by a counter-intuitive increase in G1 length, also observed in vivo. While fibroblast growth factor/extracellular signal-regulated kinase (FGF/ERK) signalling is a key regulator of ESC differentiation and PrE specification, we find it is not just responsible for ESCs heterogeneity, but also the inheritance of similar cell cycles between sisters and cousins. Taken together, our results indicate a tight relationship between transcriptional heterogeneity and cell cycle regulation in lineage specification, with primed cell populations providing a pool of flexible cell types that can be expanded in a lineage-specific fashion while allowing plasticity during early determination.
format Online
Article
Text
id pubmed-9417417
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-94174172022-08-27 Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming Perera, Marta Nissen, Silas Boye Proks, Martin Pozzi, Sara Monteiro, Rita S Trusina, Ala Brickman, Joshua M eLife Developmental Biology During embryonic development cells acquire identity as they proliferate, implying that an intrinsic facet of cell fate choice requires coupling lineage decisions to cell division. How is the cell cycle regulated to promote or suppress heterogeneity and differentiation? We explore this question combining time lapse imaging with single-cell RNA-seq in the contexts of self-renewal, priming, and differentiation of mouse embryonic stem cells (ESCs) towards the Primitive Endoderm (PrE) lineage. Since ESCs are derived from the inner cell mass (ICM) of the mammalian blastocyst, ESCs in standard culture conditions are transcriptionally heterogeneous containing dynamically interconverting subfractions primed for either of the two ICM lineages, Epiblast and PrE. Here, we find that differential regulation of cell cycle can tip the balance between these primed populations, such that naïve ESC culture promotes Epiblast-like expansion and PrE differentiation stimulates the selective survival and proliferation of PrE-primed cells. In endoderm differentiation, this change is accompanied by a counter-intuitive increase in G1 length, also observed in vivo. While fibroblast growth factor/extracellular signal-regulated kinase (FGF/ERK) signalling is a key regulator of ESC differentiation and PrE specification, we find it is not just responsible for ESCs heterogeneity, but also the inheritance of similar cell cycles between sisters and cousins. Taken together, our results indicate a tight relationship between transcriptional heterogeneity and cell cycle regulation in lineage specification, with primed cell populations providing a pool of flexible cell types that can be expanded in a lineage-specific fashion while allowing plasticity during early determination. eLife Sciences Publications, Ltd 2022-08-15 /pmc/articles/PMC9417417/ /pubmed/35969041 http://dx.doi.org/10.7554/eLife.78967 Text en © 2022, Perera et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Perera, Marta
Nissen, Silas Boye
Proks, Martin
Pozzi, Sara
Monteiro, Rita S
Trusina, Ala
Brickman, Joshua M
Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming
title Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming
title_full Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming
title_fullStr Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming
title_full_unstemmed Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming
title_short Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming
title_sort transcriptional heterogeneity and cell cycle regulation as central determinants of primitive endoderm priming
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9417417/
https://www.ncbi.nlm.nih.gov/pubmed/35969041
http://dx.doi.org/10.7554/eLife.78967
work_keys_str_mv AT pereramarta transcriptionalheterogeneityandcellcycleregulationascentraldeterminantsofprimitiveendodermpriming
AT nissensilasboye transcriptionalheterogeneityandcellcycleregulationascentraldeterminantsofprimitiveendodermpriming
AT proksmartin transcriptionalheterogeneityandcellcycleregulationascentraldeterminantsofprimitiveendodermpriming
AT pozzisara transcriptionalheterogeneityandcellcycleregulationascentraldeterminantsofprimitiveendodermpriming
AT monteiroritas transcriptionalheterogeneityandcellcycleregulationascentraldeterminantsofprimitiveendodermpriming
AT trusinaala transcriptionalheterogeneityandcellcycleregulationascentraldeterminantsofprimitiveendodermpriming
AT brickmanjoshuam transcriptionalheterogeneityandcellcycleregulationascentraldeterminantsofprimitiveendodermpriming