A transcription factor atlas of directed differentiation

Cell. 2023 Jan 5;186(1):209-229.e26. doi: 10.1016/j.cell.2022.11.026.


Transcription factors (TFs) regulate gene programs, thereby controlling diverse cellular processes and cell states. To comprehensively understand TFs and the programs they control, we created a barcoded library of all annotated human TF splice isoforms (>3,500) and applied it to build a TF Atlas charting expression profiles of human embryonic stem cells (hESCs) overexpressing each TF at single-cell resolution. We mapped TF-induced expression profiles to reference cell types and validated candidate TFs for generation of diverse cell types, spanning all three germ layers and trophoblasts. Targeted screens with subsets of the library allowed us to create a tailored cellular disease model and integrate mRNA expression and chromatin accessibility data to identify downstream regulators. Finally, we characterized the effects of combinatorial TF overexpression by developing and validating a strategy for predicting combinations of TFs that produce target expression profiles matching reference cell types to accelerate cellular engineering efforts.

Keywords: ORF overexpression; cell engineering; cellular disease modeling; combinatorial perturbation; gene regulation; genetic screening; neural progenitor; pluripotent stem cell; single cell profiling; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atlases as Topic
  • Cell Differentiation*
  • Chromatin
  • Gene Expression Regulation
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Transcription Factors* / metabolism


  • Chromatin
  • Transcription Factors