Lynette Chan

All Publications

• Transcription factor antagonism regulates heterogeneity in embryonic stem cell states MOLECULAR CELL Hu, S., Metcalf, E., Mahat, D., Chan, L., Sohal, N., Chakraborty, M., Hamilton, M., Singh, A., Singh, A., Lees, J. A., Sharp, P. A., Garg, S. 2022; 82 (23): 4410-+

  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.

  View details for DOI 10.1016/j.molcel.2022.10.022

  View details for Web of Science ID 000922730600005

  View details for PubMedID 36356583

  View details for PubMedCentralID PMC9722640