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

doi:10.1016/j.cell.2022.11.026

A transcription factor atlas of directed differentiation

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

Authors

Julia Joung¹, Sai Ma², Tristan Tay³, Kathryn R Geiger-Schuller⁴, Paul C Kirchgatterer¹, Vanessa K Verdine¹, Baolin Guo⁵, Mario A Arias-Garcia⁵, William E Allen⁶, Ankita Singh¹, Olena Kuksenko⁴, Omar O Abudayyeh¹, Jonathan S Gootenberg¹, Zhanyan Fu⁵, Rhiannon K Macrae¹, Jason D Buenrostro³, Aviv Regev⁴, Feng Zhang⁷

Affiliations

¹ Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA.
² Department of Biology, MIT, Cambridge, MA 02139, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Biology, MIT, Cambridge, MA 02139, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ McGovern Institute for Brain Research at MIT, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA; Society of Fellows, Harvard University, Cambridge, MA, USA.
⁷ Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. Electronic address: zhang@broadinstitute.org.

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.

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

Substances

Chromatin
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding