A transcription factor atlas of directed differentiation

Julia Joung, Sai Ma, Tristan Tay, Kathryn R. Geiger-Schuller, Paul C. Kirchgatterer, Vanessa K. Verdine, Baolin Guo, Mario A. Arias-Garcia, William E. Allen, Ankita Singh, Olena Kuksenko, Omar O. Abudayyeh, Jonathan S. Gootenberg, Zhanyan Fu, Rhiannon K. Macrae, Jason D. Buenrostro, Aviv Regev, Feng Zhang

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)209-229.e26
JournalCell
Volume186
Issue number1
DOIs
StatePublished - 5 Jan 2023
Externally publishedYes

Keywords

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

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