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Modulating mesendoderm competence during human germ layer differentiation

ABSTRACT: SUMMARY As pluripotent human embryonic stem cells progress toward one germ layer fate, they lose the ability to adopt alternative fates. Using a low-dimensional reaction coordinate to monitor progression toward ectoderm, we show that a differentiating stem cell’s probability of adopting a mesendodermal fate given appropriate signals falls sharply at a point along the ectoderm trajectory. We use this reaction coordinate to prospectively isolate and profile differentiating cells based on their mesendoderm competence and analyze their RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiles to identify transcription factors that control the cell’s mesendoderm competence. By modulating these key transcription factors, we can expand or contract the window of competence to adopt the mesendodermal fate along the ectodermal differentiation trajectory. The ability of the underlying gene regulatory network to modulate competence is essential for understanding human development and controlling the fate choices of stem cells in vitro. Graphical Abstract In brief The competence of human embryonic stem cells to take on mesendoderm fates is lost at a particular point along the ectoderm trajectory. Valcourt et al. analyze transcriptomics and chromatin accessibility of cell populations before and after competence loss to reveal genes whose perturbation can expand or contract mesendoderm competence.

SUBMITTER: Valcourt J

PROVIDER: S-EPMC8601596 | biostudies-literature |

REPOSITORIES: biostudies-literature

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