Mapping genotypes to chromatin accessibility profiles in single cells

• 成果类型: Article
• 署名作者: Izzo, Franco; Myers, Robert M.; Ganesan, Saravanan; Mekerishvili, Levan; Kottapalli, Sanjay; Prieto, Tamara; Eton, Elliot O.; Botella, Theo; Dunbar, Andrew J.; Bowman, Robert L.; Sotelo, Jesus; Potenski, Catherine; Mimitou, Eleni P.; Stahl, Maximilian; El Ghaity-Beckley, Sebastian; Arandela, JoAnn; Raviram, Ramya; Choi, Daniel C.; Hoffman, Ronald; Chaligne, Ronan; Abdel-Wahab, Omar; Smibert, Peter; Ghobrial, Irene M.; Scandura, Joseph M.; Marcellino, Bridget; Levine, Ross L.; Landau, Dan A.
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Rockefeller University; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Icahn School of Medicine at Mount Sinai; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Memorial Sloan Kettering Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5593
• DOI: 10.1038/s41586-024-07388-y
• 发表日期: 2024-05-30
• 页码: 1149-+
• 关键词: hematopoietic stem-cells; tyrosine kinase jak2; polycythemia-vera; fetal-hemoglobin; essential thrombocythemia; somatic mutations; self-renewal; differentiation; ruxolitinib; expression

摘要

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates(1-3). Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34(+) cells from patients with myeloproliferative neoplasms with JAK2(V617F)-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2(V617F)-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2(V617F) mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.