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Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells

View ORCID ProfileEleni P. Mimitou, View ORCID ProfileCaleb A. Lareau, View ORCID ProfileKelvin Y. Chen, Andre L. Zorzetto-Fernandes, Yusuke Takeshima, Wendy Luo, Tse-Shun Huang, View ORCID ProfileBertrand Yeung, Pratiksha I. Thakore, James Badger Wing, View ORCID ProfileKristopher L. Nazor, View ORCID ProfileShimon Sakaguchi, View ORCID ProfileLeif S. Ludwig, View ORCID ProfileVijay G. Sankaran, View ORCID ProfileAviv Regev, View ORCID ProfilePeter Smibert
doi: https://doi.org/10.1101/2020.09.08.286914
Eleni P. Mimitou
1Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
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  • For correspondence: psmibert@nygenome.org
Caleb A. Lareau
2Departments of Pathology and Genetics, Stanford University, Stanford CA, 94305
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Kelvin Y. Chen
5Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan
6Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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Andre L. Zorzetto-Fernandes
7BioLegend Inc, San Diego, CA, USA
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Yusuke Takeshima
5Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan
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Wendy Luo
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Tse-Shun Huang
7BioLegend Inc, San Diego, CA, USA
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Bertrand Yeung
7BioLegend Inc, San Diego, CA, USA
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Pratiksha I. Thakore
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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James Badger Wing
5Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan
8Laboratory of Human Immunology (Single Cell Immunology), Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan
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Kristopher L. Nazor
7BioLegend Inc, San Diego, CA, USA
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Shimon Sakaguchi
5Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan
6Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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Leif S. Ludwig
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Vijay G. Sankaran
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Aviv Regev
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
9Howard Hughes Medical Institute, Chevy Chase, MD 26309, USA
10Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
11Current address: Genentech, 1 DNA Way, South San Francisco, CA
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Peter Smibert
1Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
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ABSTRACT

Recent technological advances have enabled massively parallel chromatin profiling with single-cell Assay for Transposase Accessible Chromatin by sequencing (scATAC-seq) in thousands of individual cells. Here, we extend these approaches and present ATAC with Select Antigen Profiling by sequencing, ASAP-seq, a tool to simultaneously profile accessible chromatin and protein levels in thousands of single cells. Our approach pairs sparse scATAC-seq data with robust detection of hundreds of cell surface and intracellular protein markers and optional capture of mitochondrial DNA (mtDNA) for clonal tracking, thus concomitantly capturing three distinct modalities in single cells. Importantly, ASAP-seq uses a novel bridging approach that repurposes antibody:oligo conjugates designed for existing technologies that pair protein measurements with single cell RNA-seq. We demonstrate the utility of ASAP-seq by revealing coordinated and distinct changes in chromatin, RNA, and surface proteins during native hematopoietic differentiation, peripheral blood mononuclear cell stimulation, and as a combinatorial decoder and reporter of multiplexed perturbations in primary T cells.

Competing Interest Statement

COMPETING INTERESTS PS is listed as co-inventor on a patent related to this work (US provisional patent application 62/515-180). CAL, LSL, VGS, and AR are listed as co-inventors on a patent related to mtscATAC-seq (US provisional patent application 62/683,502). A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and ThermoFisher Scientific. From August 1, 2020, A.R. is an employee of Genentech.

Footnotes

  • ↵13 Senior author

  • https://github.com/caleblareau/asap_reproducibility

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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Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells
Eleni P. Mimitou, Caleb A. Lareau, Kelvin Y. Chen, Andre L. Zorzetto-Fernandes, Yusuke Takeshima, Wendy Luo, Tse-Shun Huang, Bertrand Yeung, Pratiksha I. Thakore, James Badger Wing, Kristopher L. Nazor, Shimon Sakaguchi, Leif S. Ludwig, Vijay G. Sankaran, Aviv Regev, Peter Smibert
bioRxiv 2020.09.08.286914; doi: https://doi.org/10.1101/2020.09.08.286914
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Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells
Eleni P. Mimitou, Caleb A. Lareau, Kelvin Y. Chen, Andre L. Zorzetto-Fernandes, Yusuke Takeshima, Wendy Luo, Tse-Shun Huang, Bertrand Yeung, Pratiksha I. Thakore, James Badger Wing, Kristopher L. Nazor, Shimon Sakaguchi, Leif S. Ludwig, Vijay G. Sankaran, Aviv Regev, Peter Smibert
bioRxiv 2020.09.08.286914; doi: https://doi.org/10.1101/2020.09.08.286914

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