Responsiveness to perturbations is a hallmark of transcription factors that maintain cell identity in vitro

Ian A. Mellis, Hailey I. Edelstein, Rachel Truitt, Yogesh Goyal, Lauren E. Beck, Orsolya Symmons, Margaret C. Dunagin, Ricardo A. Linares Saldana, Parisha P. Shah, Juan A. Pérez-Bermejo, Arun Padmanabhan, Wenli Yang, Rajan Jain*, Arjun Raj

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Identifying the particular transcription factors that maintain cell type in vitro is important for manipulating cell type. Identifying such transcription factors by their cell-type-specific expression or their involvement in developmental regulation has had limited success. We hypothesized that because cell type is often resilient to perturbations, the transcriptional response to perturbations would reveal identity-maintaining transcription factors. We developed perturbation panel profiling (P3) as a framework for perturbing cells across many conditions and measuring gene expression responsiveness transcriptome-wide. In human iPSC-derived cardiac myocytes, P3 showed that transcription factors important for cardiac myocyte differentiation and maintenance were among the most frequently upregulated (most responsive). We reasoned that one function of responsive genes may be to maintain cellular identity. We identified responsive transcription factors in fibroblasts using P3 and found that suppressing their expression led to enhanced reprogramming. We propose that responsiveness to perturbations is a property of transcription factors that help maintain cellular identity in vitro. A record of this paper's transparent peer review process is included in the supplemental information.

Original languageEnglish (US)
Pages (from-to)885-899.e8
JournalCell Systems
Volume12
Issue number9
DOIs
StatePublished - Sep 22 2021
Externally publishedYes

Keywords

  • cardiac myocytes
  • cell identity
  • fibroblasts
  • gene regulation
  • induced pluripotent stem cells
  • reprogramming
  • systems biology
  • transdifferentiation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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