Chromatin Velocity reveals epigenetic dynamics by single-cell profiling of heterochromatin and euchromatin

Martina Tedesco, Francesca Giannese, Dejan Lazarević, Valentina Giansanti, Dalia Rosano, Silvia Monzani, Irene Catalano, Elena Grassi, Eugenia R. Zanella, Oronza A. Botrugno, Leonardo Morelli, Paola Panina Bordignon, Giulio Caravagna, Andrea Bertotti, Gianvito Martino, Luca Aldrighetti, Sebastiano Pasqualato, Livio Trusolino, Davide Cittaro, Giovanni Tonon

Research output: Contribution to journalArticlepeer-review


Recent efforts have succeeded in surveying open chromatin at the single-cell level, but high-throughput, single-cell assessment of heterochromatin and its underlying genomic determinants remains challenging. We engineered a hybrid transposase including the chromodomain (CD) of the heterochromatin protein-1α (HP-1α), which is involved in heterochromatin assembly and maintenance through its binding to trimethylation of the lysine 9 on histone 3 (H3K9me3), and developed a single-cell method, single-cell genome and epigenome by transposases sequencing (scGET-seq), that, unlike single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), comprehensively probes both open and closed chromatin and concomitantly records the underlying genomic sequences. We tested scGET-seq in cancer-derived organoids and human-derived xenograft (PDX) models and identified genetic events and plasticity-driven mechanisms contributing to cancer drug resistance. Next, building upon the differential enrichment of closed and open chromatin, we devised a method, Chromatin Velocity, that identifies the trajectories of epigenetic modifications at the single-cell level. Chromatin Velocity uncovered paths of epigenetic reorganization during stem cell reprogramming and identified key transcription factors driving these developmental processes. scGET-seq reveals the dynamics of genomic and epigenetic landscapes underlying any cellular processes.

Original languageEnglish
Pages (from-to)235-244
Number of pages10
JournalNature Biotechnology
Issue number2
Publication statusPublished - Feb 2022

ASJC Scopus subject areas

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


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