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Characterizing cellular heterogeneity in chromatin state with scCUT&Tag-pro

View ORCID ProfileBingjie Zhang, View ORCID ProfileAvi Srivastava, View ORCID ProfileEleni Mimitou, View ORCID ProfileTim Stuart, View ORCID ProfileIvan Raimondi, View ORCID ProfileYuhan Hao, View ORCID ProfilePeter Smibert, View ORCID ProfileRahul Satija
doi: https://doi.org/10.1101/2021.09.13.460120
Bingjie Zhang
1New York Genome Center, New York, NY, 10013 USA
2Center for Genomics and Systems Biology, New York University, 12 Waverly Pl, New York, NY, 10003 USA
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  • ORCID record for Bingjie Zhang
Avi Srivastava
1New York Genome Center, New York, NY, 10013 USA
2Center for Genomics and Systems Biology, New York University, 12 Waverly Pl, New York, NY, 10003 USA
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Eleni Mimitou
3Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
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  • ORCID record for Eleni Mimitou
Tim Stuart
1New York Genome Center, New York, NY, 10013 USA
2Center for Genomics and Systems Biology, New York University, 12 Waverly Pl, New York, NY, 10003 USA
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Ivan Raimondi
3Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
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  • ORCID record for Ivan Raimondi
Yuhan Hao
1New York Genome Center, New York, NY, 10013 USA
2Center for Genomics and Systems Biology, New York University, 12 Waverly Pl, New York, NY, 10003 USA
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Peter Smibert
3Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
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  • ORCID record for Peter Smibert
Rahul Satija
1New York Genome Center, New York, NY, 10013 USA
2Center for Genomics and Systems Biology, New York University, 12 Waverly Pl, New York, NY, 10003 USA
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  • For correspondence: rsatija@nygenome.org
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Abstract

New technologies that profile chromatin modifications at single-cell resolution offer enormous promise for functional genomic characterization. However, the sparsity of these measurements and the challenge of integrating multiple binding maps represent significant challenges. Here we introduce scCUT&Tag-pro, a multimodal assay for profiling protein-DNA interactions coupled with the abundance of surface proteins in single cells. In addition, we introduce scChromHMM, which integrates data from multiple experiments to infer and annotate chromatin states based on combinatorial histone modification patterns. We apply these tools to perform an integrated analysis across nine different molecular modalities in circulating human immune cells. We demonstrate how these two approaches can characterize dynamic changes in the function of individual genomic elements across both discrete cell states and continuous developmental trajectories, nominate associated motifs and regulators that establish chromatin states, and identify extensive and cell type-specific regulatory priming. Finally, we demonstrate how our integrated reference can serve as a scaffold to map and improve the interpretation of additional scCUT&Tag datasets.

Competing Interest Statement

In the past three years, R.S. has worked as a consultant for Bristol-Myers Squibb, Regeneron, and Kallyope and served as an SAB member for ImmunAI, Resolve Biosciences, Nanostring, and the NYC Pandemic Response Lab. P.S. is a co-inventor of a patent related to this work.

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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 September 14, 2021.
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Characterizing cellular heterogeneity in chromatin state with scCUT&Tag-pro
Bingjie Zhang, Avi Srivastava, Eleni Mimitou, Tim Stuart, Ivan Raimondi, Yuhan Hao, Peter Smibert, Rahul Satija
bioRxiv 2021.09.13.460120; doi: https://doi.org/10.1101/2021.09.13.460120
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Characterizing cellular heterogeneity in chromatin state with scCUT&Tag-pro
Bingjie Zhang, Avi Srivastava, Eleni Mimitou, Tim Stuart, Ivan Raimondi, Yuhan Hao, Peter Smibert, Rahul Satija
bioRxiv 2021.09.13.460120; doi: https://doi.org/10.1101/2021.09.13.460120

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