Transcription factor antagonism regulates heterogeneity in embryonic stem cell states
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1-s2.0-S109727652201022X-main.pdf
Description
Published version
Size
6.81 MB
Format
Adobe PDF
Checksum (MD5)
40e97abc8fa129c937ec36fcf0f55803
Author(s)
Hu, Sofia
Metcalf, Emily
Mahat, Dig Bijay
Chan, Lynette
Sohal, Noor
Chakraborty, Meenakshi
Hamilton, Maxwell
Singh, Arundeep
Singh, Abhyudai
Lees, Jacqueline A
Date Issued
November 2022
Journal
Molecular Cell
Publisher
Elsevier BV
Citation
Hu, Sofia, Metcalf, Emily, Mahat, Dig Bijay, Chan, Lynette, Sohal, Noor et al. 2022. "Transcription factor antagonism regulates heterogeneity in embryonic stem cell states." Molecular Cell.
Version
Final published version
Abstract
Gene expression heterogeneity underlies cell states and contributes to developmental robustness. While heterogeneity can arise from stochastic transcriptional processes, the extent to which it is regulated is unclear. Here, we characterize the regulatory program underlying heterogeneity in murine embryonic stem cell (mESC) states. We identify differentially active and transcribed enhancers (DATEs) across states. DATEs regulate differentially expressed genes and are distinguished by co-binding of transcription factors Klf4 and Zfp281. In contrast to other factors that interact in a positive feedback network stabilizing mESC cell-type identity, Klf4 and Zfp281 drive opposing transcriptional and chromatin programs. Abrogation of factor binding to DATEs dampens variation in gene expression, and factor loss alters kinetics of switching between states. These results show antagonism between factors at enhancers results in gene expression heterogeneity and formation of cell states, with implications for the generation of diverse cell types during development.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1016/j.molcel.2022.10.022
