Mapping genotypes to chromatin accessibility profiles in single cells

Franco Izzo (), Robert M. Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Tamara Prieto, Elliot O. Eton, Theo Botella, Andrew J. Dunbar, Robert L. Bowman, Jesus Sotelo, Catherine Potenski, Eleni P. Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, JoAnn Arandela, Ramya Raviram, Daniel C. Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M. Ghobrial, Joseph M. Scandura, Bridget Marcellino, Ross L. Levine and Dan A. Landau ()
Additional contact information
Franco Izzo: New York Genome Center
Robert M. Myers: New York Genome Center
Saravanan Ganesan: New York Genome Center
Levan Mekerishvili: New York Genome Center
Sanjay Kottapalli: New York Genome Center
Tamara Prieto: New York Genome Center
Elliot O. Eton: New York Genome Center
Theo Botella: New York Genome Center
Andrew J. Dunbar: Memorial Sloan Kettering Cancer Center
Robert L. Bowman: Memorial Sloan Kettering Cancer Center
Jesus Sotelo: New York Genome Center
Catherine Potenski: New York Genome Center
Eleni P. Mimitou: New York Genome Center
Maximilian Stahl: Memorial Sloan Kettering Cancer Center
Sebastian El Ghaity-Beckley: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
JoAnn Arandela: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Ramya Raviram: New York Genome Center
Daniel C. Choi: Weill Cornell Medicine
Ronald Hoffman: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Ronan Chaligné: New York Genome Center
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center
Peter Smibert: New York Genome Center
Irene M. Ghobrial: Dana-Farber Cancer Institute
Joseph M. Scandura: Weill Cornell Medicine
Bridget Marcellino: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Ross L. Levine: Memorial Sloan Kettering Cancer Center
Dan A. Landau: New York Genome Center

Nature, 2024, vol. 629, issue 8014, 1149-1157

Abstract: Abstract In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1–3. 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 JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-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 JAK2V617F 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.

Date: 2024
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DOI: 10.1038/s41586-024-07388-y

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