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Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming

View ORCID ProfileKenji Kamimoto, View ORCID ProfileMohd Tayyab Adil, View ORCID ProfileKunal Jindal, View ORCID ProfileChristy M. Hoffmann, View ORCID ProfileWenjun Kong, View ORCID ProfileXue Yang, View ORCID ProfileSamantha A. Morris
doi: https://doi.org/10.1101/2022.07.01.497374
Kenji Kamimoto
1Department of Developmental Biology, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
2Department of Genetics, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
3Center of Regenerative Medicine. Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
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Mohd Tayyab Adil
1Department of Developmental Biology, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
2Department of Genetics, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
3Center of Regenerative Medicine. Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
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Kunal Jindal
1Department of Developmental Biology, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
2Department of Genetics, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
3Center of Regenerative Medicine. Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
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Christy M. Hoffmann
1Department of Developmental Biology, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
2Department of Genetics, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
3Center of Regenerative Medicine. Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
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Wenjun Kong
1Department of Developmental Biology, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
2Department of Genetics, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
3Center of Regenerative Medicine. Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
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Xue Yang
1Department of Developmental Biology, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
2Department of Genetics, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
3Center of Regenerative Medicine. Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
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Samantha A. Morris
1Department of Developmental Biology, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
2Department of Genetics, Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
3Center of Regenerative Medicine. Washington University School of Medicine in St. Louis. 660 S. Euclid Avenue, Campus Box 8103, St. Louis, MO 63110, USA
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  • For correspondence: s.morris@wustl.edu
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Summary

In direct lineage reprogramming, transcription factor (TF) overexpression reconfigures Gene Regulatory Networks (GRNs) to convert cell identities between fully differentiated cell types. We previously developed CellOracle, a computational pipeline that integrates single-cell transcriptome and epigenome profiles to infer GRNs. CellOracle leverages these inferred GRNs to simulate gene expression changes in response to TF perturbation, enabling network re-configuration during reprogramming to be interrogated in silico. Here, we integrate CellOracle analysis with lineage tracing of fibroblast to induced endoderm progenitor (iEP) conversion, a prototypical direct lineage reprogramming paradigm. By linking early network state to reprogramming success or failure, we reveal distinct network configurations underlying different reprogramming outcomes. Using these network analyses and in silico simulation of TF perturbation, we identify new factors to coax cells into successfully converting cell identity, uncovering a central role for the AP-1 subunit Fos with the Hippo signaling effector, Yap1. Together, these results demonstrate the efficacy of CellOracle to infer and interpret cell-type-specific GRN configurations at high resolution, providing new mechanistic insights into the regulation and reprogramming of cell identity.

Competing Interest Statement

Samantha Morris is co-founder of CapyBio LLC.

Footnotes

  • ↵4 Calico Life Sciences LLC.

  • https://github.com/morris-lab/CellOracle

  • https://github.com/morris-lab/Capybara

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-NC-ND 4.0 International license.
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Posted July 03, 2022.
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Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming
Kenji Kamimoto, Mohd Tayyab Adil, Kunal Jindal, Christy M. Hoffmann, Wenjun Kong, Xue Yang, Samantha A. Morris
bioRxiv 2022.07.01.497374; doi: https://doi.org/10.1101/2022.07.01.497374
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Gene Regulatory Network Reconfiguration in Direct Lineage Reprogramming
Kenji Kamimoto, Mohd Tayyab Adil, Kunal Jindal, Christy M. Hoffmann, Wenjun Kong, Xue Yang, Samantha A. Morris
bioRxiv 2022.07.01.497374; doi: https://doi.org/10.1101/2022.07.01.497374

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