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

• Published in: Nature biotechnology Vol. 40; no. 2; pp. 235 - 244
• Main Authors: Tedesco, Martina, Giannese, Francesca, Lazarević, Dejan, Giansanti, Valentina, Rosano, Dalia, Monzani, Silvia, Catalano, Irene, Grassi, Elena, Zanella, Eugenia R., Botrugno, Oronza A., Morelli, Leonardo, Panina Bordignon, Paola, Caravagna, Giulio, Bertotti, Andrea, Martino, Gianvito, Aldrighetti, Luca, Pasqualato, Sebastiano, Trusolino, Livio, Cittaro, Davide, Tonon, Giovanni
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2022; Nature Publishing Group
• Subjects: 631/114/2397; 631/1647/2210/2211; 631/337/2569; 631/378/2183/2182; 631/67/69; Agriculture; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cancer; Chromatin; Chromatin - genetics; DNA probes; Drug resistance; Epigenesis, Genetic - genetics; Epigenetics; Euchromatin; Euchromatin - genetics; Gene mapping; Genomics; Heterochromatin; Heterochromatin - genetics; Histones; Humans; Life Sciences; Lysine; Organoids; Stem cells; Transcription factors; Transposase; Transposases - genetics; Velocity; Xenografts; Xenotransplantation
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/s41587-021-01031-1

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. Single-cell mapping of heterochromatin and euchromatin using chromatin velocity defines trajectories of epigenetic modifications.