Journal Article

A comprehensive library of human transcription factors for cell fate engineering

Graveline, Amanda, Dysart, Matthew, Saylor, Wren, Shipman, Seth L., Rojo Arias, Jesus Eduardo, Huang, Jeremy Y., Vidal, Marc, Kohman, Richie E., Busskamp, Volker, Melero-Martin, Juan M., Swiersy, Anka, Appleton, Evan, Vernet, Andyna, Ng, Alex H. M., Leeper, Kathleen, Taipale, Jussi, Pasquini, Giovanni, Church, George M., Khoshakhlagh, Parastoo, Wang, Kai, Hill, David E., Kiaee, Kiavash

2021

Overview

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. A library of human transcription factor genes is screened for differentiation of human pluripotent stem cells.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/532/1360 / 631/61/2035 / 631/61/2320 / Agriculture / Alternative Splicing / Bioinformatics / Biology / Biomechanics / Biomedical and Life Sciences / Biomedical engineering / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Cell Differentiation / Cell Engineering / Cell fate / Cells, Cultured / Cellular Reprogramming Techniques - methods / Coculture Techniques / Combinatorial analysis / Comparative analysis / Developmental biology / Fibroblasts / Genes / Genetic aspects / Genomic libraries / Humans / Identification and classification / Isoforms / Libraries / Life Sciences / Methods / Myelination / Oligodendrocytes / Oligodendroglia - cytology / Oligodendroglia - metabolism / Organoids / Parallel programming / Pluripotency / Pluripotent Stem Cells - cytology / Pluripotent Stem Cells - metabolism / Resource / Screening / Stem cells / Systems Biology / Transcription factors / Transcription Factors - genetics