Transcription factor co-expression mediates lineage priming for embryonic and extra-embryonic differentiation

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In early mammalian development, cleavage stage blastomeres and inner cell mass (ICM) cells co-express embryonic and extra-embryonic transcriptional determinants. Using a protein-based double reporter we identify an embryonic stem cell (ESC) population that co-expresses the extra-embryonic factor GATA6 alongside the embryonic factor SOX2. Based on single cell transcriptomics, we find this population resembles the unsegregated ICM, exhibiting enhanced differentiation potential for endoderm while maintaining epiblast competence. To relate transcription factor binding in these cells to future fate, we describe a complete enhancer set in both ESCs and naive extra-embryonic endoderm stem cells and assess SOX2 and GATA6 binding at these elements in the ICM-like ESC sub-population. Both factors support cooperative recognition in these lineages, with GATA6 bound alongside SOX2 on a fraction of pluripotency enhancers and SOX2 alongside GATA6 more extensively on endoderm enhancers, suggesting that cooperative binding between these antagonistic factors both supports self-renewal and prepares progenitor cells for later differentiation.
OriginalsprogEngelsk
TidsskriftStem Cell Reports
Vol/bind19
Udgave nummer2
Sider (fra-til)174-186
Antal sider13
ISSN2213-6711
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank Paul van Dieken and Gelo de la Cruz for flow cytometry and FACS support and expertise. We thank Michaela M. Rothová, Helen Neil, and Magali Michaut for technical expertise and support with the scRNA-seq and CUT&RUN sequencing. We thank Javier Martin Gonzalez, Ricardo Alonso Laguna Barraza, and all the transgenics platform facility for technical assistance and providing mouse embryos. We thank Jutta Bulkescher and the reNEW Imaging Platform for training, technical expertise, support, and the use of microscopes. We thank Jose Alejandro Herrera Romero and Sarah Louise Lundregan for bioinformatics advice. Last, we thank the entire Brickman laboratory, especially Molly P. Lowndes and Robert A. Bone, for critical discussion. Work in the Brickman laboratory was supported by Lundbeck Foundation ( R198-2015-412 , R370-2021-617 and R400-2022-769 ), Independent Research Fund Denmark ( DFF-8020-00100B, DFF-0134-00022B , and DFF-2034-00025B ), and the Danish National Research Foundation (D NRF116 ). A.R.R. and M.Pe. were supported by Lundbeck Foundation PhD studentships ( R208-2015-2872 and R286-2018-1534 ). The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) is supported by the Novo Nordisk Foundation, grant number NNF21CC0073729 , and previously NNF17CC0027852 .

Publisher Copyright:
© 2023 The Author(s)

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