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

View ORCID ProfileIan A. Mellis, View ORCID ProfileHailey I. Edelstein, Rachel Truitt, View ORCID ProfileLauren E. Beck, View ORCID ProfileOrsolya Symmons, View ORCID ProfileYogesh Goyal, Margaret C. Dunagin, View ORCID ProfileRicardo A. Linares Saldana, Parisha P. Shah, View ORCID ProfileWenli Yang, View ORCID ProfileRajan Jain, View ORCID ProfileArjun Raj
doi: https://doi.org/10.1101/2020.06.11.147207
Ian A. Mellis
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
2Genomics and Computational Biology Group, University of Pennsylvania, Philadelphia, PA
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  • ORCID record for Ian A. Mellis
Hailey I. Edelstein
3Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA
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Rachel Truitt
3Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA
4Department of Medicine, University of Pennsylvania, Philadelphia, PA
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Lauren E. Beck
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Orsolya Symmons
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Yogesh Goyal
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Margaret C. Dunagin
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Ricardo A. Linares Saldana
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA
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Parisha P. Shah
4Department of Medicine, University of Pennsylvania, Philadelphia, PA
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA
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Wenli Yang
3Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA
4Department of Medicine, University of Pennsylvania, Philadelphia, PA
6Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Rajan Jain
3Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA
4Department of Medicine, University of Pennsylvania, Philadelphia, PA
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA
6Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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  • For correspondence: arjunrajlab@gmail.com jainr@pennmedicine.upenn.edu
Arjun Raj
1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
2Genomics and Computational Biology Group, University of Pennsylvania, Philadelphia, PA
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  • For correspondence: arjunrajlab@gmail.com jainr@pennmedicine.upenn.edu
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Abstract

Our ability to identify the particular transcription factors that maintain cell type is limited. Identification of factors by their cell type-specific expression or their participation in developmental regulation has been only modestly successful. We hypothesized that because cell type is often resilient to perturbations, the transcriptional response to perturbations would identify identity-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 one potential 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 efficiency. We propose that responsiveness to perturbations is a property of factors that help maintain cellular identity.

Competing Interest Statement

AR receives patent royalties from LGC/Biosearch Technologies related to Stellaris RNA FISH probes.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 30, 2020.
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Responsiveness to perturbations is a hallmark of transcription factors that maintain cell identity
Ian A. Mellis, Hailey I. Edelstein, Rachel Truitt, Lauren E. Beck, Orsolya Symmons, Yogesh Goyal, Margaret C. Dunagin, Ricardo A. Linares Saldana, Parisha P. Shah, Wenli Yang, Rajan Jain, Arjun Raj
bioRxiv 2020.06.11.147207; doi: https://doi.org/10.1101/2020.06.11.147207
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Responsiveness to perturbations is a hallmark of transcription factors that maintain cell identity
Ian A. Mellis, Hailey I. Edelstein, Rachel Truitt, Lauren E. Beck, Orsolya Symmons, Yogesh Goyal, Margaret C. Dunagin, Ricardo A. Linares Saldana, Parisha P. Shah, Wenli Yang, Rajan Jain, Arjun Raj
bioRxiv 2020.06.11.147207; doi: https://doi.org/10.1101/2020.06.11.147207

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