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Multiomic single-cell lineage tracing to dissect fate-specific gene regulatory programs

View ORCID ProfileKunal Jindal, View ORCID ProfileMohd Tayyab Adil, View ORCID ProfileNaoto Yamaguchi, View ORCID ProfileXue Yang, View ORCID ProfileHelen C. Wang, View ORCID ProfileKenji Kamimoto, View ORCID ProfileGuillermo C. Rivera-Gonzalez, View ORCID ProfileSamantha A. Morris
doi: https://doi.org/10.1101/2022.10.23.512790
Kunal Jindal
1Department of Developmental Biology, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
2Department of Genetics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
3Center of Regenerative Medicine, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Mohd Tayyab Adil
1Department of Developmental Biology, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
2Department of Genetics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
3Center of Regenerative Medicine, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Naoto Yamaguchi
1Department of Developmental Biology, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
2Department of Genetics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
3Center of Regenerative Medicine, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Xue Yang
1Department of Developmental Biology, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
2Department of Genetics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
3Center of Regenerative Medicine, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Helen C. Wang
4Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Kenji Kamimoto
1Department of Developmental Biology, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
2Department of Genetics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
3Center of Regenerative Medicine, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Guillermo C. Rivera-Gonzalez
1Department of Developmental Biology, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
2Department of Genetics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
3Center of Regenerative Medicine, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Samantha A. Morris
1Department of Developmental Biology, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
2Department of Genetics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
3Center of Regenerative Medicine, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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  • For correspondence: s.morris@wustl.edu
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Abstract

Complex gene regulatory mechanisms underlie differentiation and reprogramming. Contemporary single-cell lineage tracing (scLT) methods use expressed, heritable DNA barcodes to combine cell lineage readout with single-cell transcriptomics enabling high-resolution analysis of cell states while preserving lineage relationships. However, reliance on transcriptional profiling limits their adaptation to an ever-expanding tool kit of multiomic single-cell assays. With CellTag-multi, we present a novel approach for independently profiling lineage barcodes with single-cell chromatin accessibility without relying on co-assay of transcriptional state, paving the way for truly multiomic lineage tracing. We validate CellTag-multi in mouse hematopoiesis, characterizing transcriptional and epigenomic lineage priming across progenitor cell populations. In direct reprogramming of fibroblasts to endoderm progenitors, we use CellTag-multi to comprehensively link early cell state with reprogramming outcomes, identifying core regulatory programs underlying on-target and off-target reprogramming. Further, we reveal the Transcription Factor (TF) Zfp281 as a novel regulator of reprogramming outcome, biasing cells towards an off-target mesenchymal fate via its regulation of TGF-β signaling. Together, these results establish CellTag-multi as a novel lineage tracing method compatible with multiple single-cell modalities and demonstrate its utility in revealing fate-specifying gene regulatory changes across diverse paradigms of differentiation and reprogramming.

Competing Interest Statement

S.A.M. and G.R.G. are co-founders of CapyBio LLC.

Footnotes

  • Additional analysis of scATAC-seq based lineage tracing has been added.

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 December 03, 2022.
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Multiomic single-cell lineage tracing to dissect fate-specific gene regulatory programs
Kunal Jindal, Mohd Tayyab Adil, Naoto Yamaguchi, Xue Yang, Helen C. Wang, Kenji Kamimoto, Guillermo C. Rivera-Gonzalez, Samantha A. Morris
bioRxiv 2022.10.23.512790; doi: https://doi.org/10.1101/2022.10.23.512790
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Multiomic single-cell lineage tracing to dissect fate-specific gene regulatory programs
Kunal Jindal, Mohd Tayyab Adil, Naoto Yamaguchi, Xue Yang, Helen C. Wang, Kenji Kamimoto, Guillermo C. Rivera-Gonzalez, Samantha A. Morris
bioRxiv 2022.10.23.512790; doi: https://doi.org/10.1101/2022.10.23.512790

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