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
JournalNat Biotechnol
Issue number2
Publication statusPublished - Feb 2022


  • Chromatin/genetics
  • Epigenesis, Genetic/genetics
  • Euchromatin/genetics
  • Heterochromatin/genetics
  • Humans
  • Transposases/genetics


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