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Mapping Transcription Factor-Nucleosome Dynamics from Plasma cfDNA

Satyanarayan Rao, Amy L. Han, Alexis Zukowski, Etana Kopin, Carol A. Sartorius, Peter Kabos, View ORCID ProfileSrinivas Ramachandran
doi: https://doi.org/10.1101/2021.04.14.439883
Satyanarayan Rao
1Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine
2RNA Bioscience Initiative, University of Colorado School of Medicine
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Amy L. Han
4Department of Medicine/Division of Medical Oncology, University of Colorado School of Medicine
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Alexis Zukowski
1Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine
2RNA Bioscience Initiative, University of Colorado School of Medicine
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Etana Kopin
4Department of Medicine/Division of Medical Oncology, University of Colorado School of Medicine
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Carol A. Sartorius
5Department of Pathology, University of Colorado School of Medicine
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Peter Kabos
2RNA Bioscience Initiative, University of Colorado School of Medicine
4Department of Medicine/Division of Medical Oncology, University of Colorado School of Medicine
6University of Colorado Cancer Center
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  • For correspondence: peter.kabos@cuanschutz.edu srinivas.ramachandran@cuanschutz.edu
Srinivas Ramachandran
1Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine
2RNA Bioscience Initiative, University of Colorado School of Medicine
6University of Colorado Cancer Center
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  • ORCID record for Srinivas Ramachandran
  • For correspondence: peter.kabos@cuanschutz.edu srinivas.ramachandran@cuanschutz.edu
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Abstract

Cell-free DNA (cfDNA) contains a composite map of the epigenomes of its cells-of-origin. Tissue-specific transcription factor (TF) binding inferred from cfDNA could enable us to track disease states in humans in a minimally invasive manner. Here, by enriching for short cfDNA fragments, we directly map TF footprints at single binding sites from plasma. We show that the enrichment of TF footprints in plasma reflects the binding strength of the TF in cfDNA tissue-of-origin. Based on this principle, we were able to identify the subset of genome-wide binding sites for selected TFs that leave TF-specific footprints in plasma. These footprints enabled us to not only identify the tissue-of-origin of cfDNA but also map the chromatin structure around the factor-bound sites in their cells-of-origin. To ask if we can use these plasma TF footprints to map cancer states, we first defined pure tumor TF signatures in plasma in vivo using estrogen receptor-positive (ER+) breast cancer xenografts. We found that the tumor-specific cfDNA protections of ER-α could distinguish WT, ER-amplified, and ER-mutated xenografts. Further, tumor-specific cfDNA protections of ER-α and FOXA1 reflect TF-specific accessibility across human breast tumors, demonstrating our ability to capture tumor TF binding in plasma. We then scored TF binding in human plasma samples and identified specific binding sites whose plasma TF protections can identify the presence of cancer and specifically breast cancer. Thus, plasma TF footprints enable minimally invasive mapping of the regulatory landscape of cancer in humans.

Competing Interest Statement

P.K., S. Ramachandran, S. Rao, A.Z., and A.H. are listed as co-inventors on a patent application related to this work (US provisional patent application 63/124179).

Footnotes

  • https://github.com/satyanarayan-rao/tf_nucleosome_dynamics

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 April 15, 2021.
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Mapping Transcription Factor-Nucleosome Dynamics from Plasma cfDNA
Satyanarayan Rao, Amy L. Han, Alexis Zukowski, Etana Kopin, Carol A. Sartorius, Peter Kabos, Srinivas Ramachandran
bioRxiv 2021.04.14.439883; doi: https://doi.org/10.1101/2021.04.14.439883
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Mapping Transcription Factor-Nucleosome Dynamics from Plasma cfDNA
Satyanarayan Rao, Amy L. Han, Alexis Zukowski, Etana Kopin, Carol A. Sartorius, Peter Kabos, Srinivas Ramachandran
bioRxiv 2021.04.14.439883; doi: https://doi.org/10.1101/2021.04.14.439883

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