Mapping genotypes to chromatin accessibility profiles in single cells Journal Article

   

Authors:	Izzo, F.; Myers, R. M.; Ganesan, S.; Mekerishvili, L.; Kottapalli, S.; Prieto, T.; Eton, E. O.; Botella, T.; Dunbar, A. J.; Bowman, R. L.; Sotelo, J.; Potenski, C.; Mimitou, E. P.; Stahl, M.; El Ghaity-Beckley, S.; Arandela, J.; Raviram, R.; Choi, D. C.; Hoffman, R.; Chaligné, R.; Abdel-Wahab, O.; Smibert, P.; Ghobrial, I. M.; Scandura, J. M.; Marcellino, B.; Levine, R. L.; Landau, D. A.
Article Title:	Mapping genotypes to chromatin accessibility profiles in single cells
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. © The Author(s), under exclusive licence to Springer Nature Limited 2024.
Keywords:	controlled study; protein expression; myeloproliferative disorders; myelofibrosis; human cell; sequence analysis; genetics; mutation; myeloproliferative disorder; janus kinase 2; nonhuman; polymerase chain reaction; mouse; cytology; metabolism; cd34 antigen; gene expression; erythroid precursor cell; protein; genotype; gene frequency; autologous stem cell transplantation; pathology; transcriptomics; gene mapping; epigenetics; chromatin; epigenesis, genetic; hematopoietic stem cells; tamoxifen; fc receptor; cytokine production; immunophenotyping; genome; hematopoiesis; upregulation; hematopoietic stem cell; fluorescence activated cell sorting; genetic epigenesis; antigens, cd34; rna polymerase ii; megakaryocyte; encapsulation; rna splicing; polycythemia vera; thrombocythemia; transcription factor gata 1; downstream processing; rna sequence; mitochondrial dna; megakaryocytes; jak2 protein, human; dna isolation; cell; genotyping; lymphoid cell; single cell analysis; single-cell analysis; gene ontology; accessibility; mitochondrial genome; epigenome; mapping method; ruxolitinib; genotyping techniques; humans; human; male; female; article; nested polymerase chain reaction
Journal Title:	Nature
Volume:	629
Issue:	8014
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2024-05-30
Start Page:	1149
End Page:	1157
Language:	English
DOI:	10.1038/s41586-024-07388-y
PUBMED:	38720070
PROVIDER:	scopus
PMCID:	PMC11139586
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85192776644&doi=10.1038%2fs41586-024-07388-y&partnerID=40&md5=237326406d03103e96f7c93911ab9b5d
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/217046