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Nanobody-tethered transposition allows for multifactorial chromatin profiling at single-cell resolution

View ORCID ProfileTim Stuart, View ORCID ProfileStephanie Hao, View ORCID ProfileBingjie Zhang, Levan Mekerishvili, View ORCID ProfileDan A Landau, View ORCID ProfileSilas Maniatis, View ORCID ProfileRahul Satija, View ORCID ProfileIvan Raimondi
doi: https://doi.org/10.1101/2022.03.08.483436
Tim Stuart
2Center for Genomics and Systems Biology, New York University, New York City, NY
3New York Genome Center, New York City, NY
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Stephanie Hao
1Technology Innovation Lab, New York Genome Center, New York City, NY
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Bingjie Zhang
2Center for Genomics and Systems Biology, New York University, New York City, NY
3New York Genome Center, New York City, NY
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Levan Mekerishvili
3New York Genome Center, New York City, NY
4Weill Cornell Medicine, New York City, NY
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Dan A Landau
3New York Genome Center, New York City, NY
4Weill Cornell Medicine, New York City, NY
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Silas Maniatis
1Technology Innovation Lab, New York Genome Center, New York City, NY
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Rahul Satija
2Center for Genomics and Systems Biology, New York University, New York City, NY
3New York Genome Center, New York City, NY
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Ivan Raimondi
1Technology Innovation Lab, New York Genome Center, New York City, NY
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  • ORCID record for Ivan Raimondi
  • For correspondence: iraimondi@nygenome.org
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Abstract

Chromatin states are functionally defined by a complex combination of histone modifications, transcription factor binding, DNA accessibility, and other factors. However, most current single-cell-resolution methods are unable to measure more than one aspect of chromatin state in a single experiment, limiting our ability to accurately measure chromatin states. Here, we introduce nanobody-tethered transposition followed by sequencing (NTT-seq), a new assay capable of measuring the genome-wide presence of multiple histone modifications and protein-DNA binding sites at single-cell resolution. NTT-seq utilizes recombinant Tn5 transposase fused to a set of secondary nanobodies (nb). Each nb-Tn5 fusion protein specifically binds to different immunoglobulin-G antibodies, enabling a mixture of primary antibodies binding different epitopes to be used in a single experiment. We apply bulk- and single-cell NTT-seq to generate high-resolution multimodal maps of chromatin states in cell culture and in cells of the human immune system, demonstrating the high accuracy and sensitivity of the method. We further extend NTT-seq to enable simultaneous profiling of cell-surface protein expression alongside multimodal chromatin states to study cells of the immune system.

Competing Interest Statement

In the past 3 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. I.R. and S.M. have filed a patent application based on this work (US Provisional Application No. 63/276,533). The remaining authors declare no competing interests.

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 4.0 International license.
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Posted March 09, 2022.
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Nanobody-tethered transposition allows for multifactorial chromatin profiling at single-cell resolution
Tim Stuart, Stephanie Hao, Bingjie Zhang, Levan Mekerishvili, Dan A Landau, Silas Maniatis, Rahul Satija, Ivan Raimondi
bioRxiv 2022.03.08.483436; doi: https://doi.org/10.1101/2022.03.08.483436
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Nanobody-tethered transposition allows for multifactorial chromatin profiling at single-cell resolution
Tim Stuart, Stephanie Hao, Bingjie Zhang, Levan Mekerishvili, Dan A Landau, Silas Maniatis, Rahul Satija, Ivan Raimondi
bioRxiv 2022.03.08.483436; doi: https://doi.org/10.1101/2022.03.08.483436

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