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

Our ability to identify the particular transcription factors that maintain cell type is limited. Identification of factors by the tissue-specificity of their expression or their participation in developmental regulation has been only modestly successful. We hypothesized that because cell type is resilient to perturbations, the transcriptional response to perturbations would identify lineage-maintaining factors. We developed Perturbation Panel Profiling (P3) as a framework for perturbing cells in dozens of conditions and measuring gene expression responsiveness transcriptome-wide. Applying P3 to human iPSC-derived cardiac myocytes showed that transcription factors known to function in cardiac differentiation and maintenance were among the most frequently up-regulated (most responsive). We reasoned that responsive genes may serve as lineage-maintaining factors. We identified responsive transcription factors in fibroblasts using P3 and found that suppressing their expression led to enhanced reprogramming efficiency. We propose that responsiveness to perturbations is a key property associated with factors that maintain cellular identity.