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

Research output: Contribution to journalArticlepeer-review


Technologies that profile chromatin modifications at single-cell resolution offer enormous promise for functional genomic characterization, but the sparsity of the measurements and integrating multiple binding maps represent substantial challenges. Here we introduce single-cell (sc)CUT&Tag-pro, a multimodal assay for profiling protein–DNA interactions coupled with the abundance of surface proteins in single cells. In addition, we introduce single-cell ChromHMM, 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.

Original languageEnglish (US)
Pages (from-to)1220-1230
Number of pages11
JournalNature Biotechnology
Issue number8
StatePublished - Aug 2022


  • Chromatin/genetics
  • Chromatin Immunoprecipitation
  • DNA
  • Genomics
  • Histones/genetics
  • Humans

ASJC Scopus subject areas

  • Applied Microbiology and Biotechnology
  • Bioengineering
  • Molecular Medicine
  • Biotechnology
  • Biomedical Engineering


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