A comprehensive library of human transcription factors for cell fate engineering

Abstract

Human pluripotent stem cells (hPSCs) offer an unprecedented opportunity to model diverse cell types and tissues. To enable systematic exploration of the programming landscape mediated by transcription factors (TFs), we present the Human TFome, a comprehensive library containing 1,564 TF genes and 1,732 TF splice isoforms. By screening the library in three hPSC lines, we discovered 290 TFs, including 241 that were previously unreported, that induce differentiation in 4 days without alteration of external soluble or biomechanical cues. We used four of the hits to program hPSCs into neurons, fibroblasts, oligodendrocytes and vascular endothelial-like cells that have molecular and functional similarity to primary cells. Our cell-autonomous approach enabled parallel programming of hPSCs into multiple cell types simultaneously. We also demonstrated orthogonal programming by including oligodendrocyte-inducible hPSCs with unmodified hPSCs to generate cerebral organoids, which expedited in situ myelination. Large-scale combinatorial screening of the Human TFome will complement other strategies for cell engineering based on developmental biology and computational systems biology.

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Fig. 1: Creation of the Human TFome expression library and its application for cell fate engineering.
Fig. 2: ATOH1 induces neurons and NKX3-1 induces fibroblasts in lineage-independent media.
Fig. 3: ETV2 isoform 2 induces vascular endothelial-like cells that form perfusable blood vessels in vivo.
Fig. 4: Parallel programming enables simultaneous differentiation of multiple cell types in the same dish.
Fig. 5: SOX9 induces oligodendrocytes that engraft and form compact myelin in vivo and in cerebral organoids.

Data availability.

Next-generation sequencing data that support the findings of the study are available in the Gene Expression Omnibus using accession code GSE159786.

Code availability

The code that supports the findings of this study is available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank J. Aach, M. O. Karl, R. Kalhor, N. Ostrov and H. Lee for critical feedback and the Church and Busskamp laboratories for support. We acknowledge technical support from the Harvard Biopolymers Facility, the Harvard Division of Immunology Flow Cytometry Core Facility, the Beth Israel Deaconess Medical Center Flow Cytometry Core, the Wyss Flow Cytometry and Microscopy Core, M. Ericsson and P. Coughlin at the Harvard Medical School Electron Microscopy Facility, M. T. Gianatasio at the Dana-Farber/Harvard Cancer Center Specialized Histopathology Core and Rodent Histopathology Core (both supported, in part, by National Cancer Institute Cancer Center Support grant NIH 5 P30 CA06516) and Harvard Medical School Orchestra Research Computing. We also thank the TU Dresden Center for Molecular and Cellular Bioengineering Advanced Imaging, Deep Sequencing, Flow Cytometry and Stem Cell Engineering core facilities. We would also like to thank J. Gray’s laboratory for electrophysiology support, S. Jeanty and J. Lee (Church lab, Harvard Medical School) for the PGP1 Sendai virus hiPSC line, G. Sheynkman and W. Glindmeyer for helpful discussions, A. Jolma, K. Nitta and K. Said for technical assistance and M. Lemieux and J. McDade for their support in depositing the library to Addgene. A.H.M.N. was supported by an NSERC Postgraduate Fellowship and a Peter and Carolyn Lynch Foundation Fellowship. J.E.R.A. was supported by the DIGS-BB program. S.L.S. is a Shurl and Kay Curci Foundation Fellow of the Life Sciences Research Foundation. The Ellison Foundation and Institute Sponsored Research funds from the DFCI Strategic Initiative supported M.V. and D.E.H. The project was supported by the Volkswagen Foundation (Freigeist - A110720), the European Research Council (ERC-StG-678071 - ProNeurons) and the Deutsche Forschungsgemeinschaft (SPP2127, EXC-2068-390729961 - Cluster of Excellence - Physics of Life at TU Dresden and EXC-2151-390873048 – Cluster of Excellence – ImmunoSensation2 at the University of Bonn) to V.B. G.M.C. acknowledges funding from National Human Genome Research Institute grants P50 HG005550 ‘Center for Casual Variation’, RM1 HG008525 ‘Center for Genomically Engineered Organs’, the Simons Foundation for Autism Research Initiative (368485), the Blavatnik Biomedical Accelerator at Harvard University, the FunGCAT program from the Office of the Director of National Intelligence Intelligence Advanced Research Projects Activity, via the Army Research Office, under federal award no. W911NF-17-2-0089 and research funding from R. Merkin and the Merkin Family Foundation.

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Contributions

A.H.M.N., P.K., V.B. and G.M.C. conceived the idea, led the study and designed all experiments. A.H.M.N. and P.K. performed most of the experiments and analyses, with significant technical contributions from J.E.R.A, G.P., K.W., A.S., S.L.S., E.A., K.K., R.E.K., A.V., M.D., K.L., W.S., J.Y.H., A.G., J.T., D.E.H., M.V. and J.M.M.-M. V.B. and G.M.C. oversaw the study. A.H.M.N., P.K. and V.B. wrote the manuscript with input and feedback from all authors.

Corresponding authors

Correspondence to Volker Busskamp or George M. Church.

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Competing interests

A.H.M.N., P.K., V.B. and G.M.C. are inventors on patents filed by the Presidents and Fellows of Harvard College. Full disclosure for G.M.C. is available at http://arep.med.harvard.edu/gmc/tech.html. A.H.M.N., P.K. and G.M.C. are co-founders of and have equity in GC Therapeutics, Inc. No reagents or funding from GC Therapeutics were used in this study.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–7

Reporting Summary

Supplementary Table 1

TFs in the Human TFome

Supplementary Table 2

TFome screen sequencing statistics

Supplementary Table 3

TFome screen differentiation scores

Supplementary Table 4

Novelty and tissue expression of 290 TF hits

Supplementary Table 5

RNA-seq statistics and expression profiles

Supplementary Table 6

TFs involved in oligodendrocyte development

Supplementary Table 7

Exact P values for statistical tests

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Ng, A.H.M., Khoshakhlagh, P., Rojo Arias, J.E. et al. A comprehensive library of human transcription factors for cell fate engineering. Nat Biotechnol (2020). https://doi.org/10.1038/s41587-020-0742-6

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