Valcourt JR, Huang RE, Kundu S, Venkatasubramanian D, Kingston RE, Ramanathan S. 2021. Modulating mesendoderm competence during human germ layer differentiation. Cell reports. 37(6):109990. Pubmed: 34758327 DOI:S2211-1247(21)01469-8


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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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Sharad Ramanathan investigates how multi-potent stem cells make fate decisions to give rise to complex human tissues, and how the dynamics of key neurons in the nervous system drive behavioral decisions.

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