Faculty, Staff and Student Publications

Publication Date

5-1-2024

Journal

Nature

DOI

10.1038/s41586-024-07388-y

PMID

38720070

PMCID

PMC11139586

PubMedCentral® Posted Date

1-8-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Animals, Female, Humans, Male, Mice, Antigens, CD34, Cell Differentiation, Chromatin, Epigenesis, Genetic, Epigenome, Genome, Mitochondrial, Genotype, Genotyping Techniques, Hematopoiesis, Hematopoietic Stem Cells, Inflammation, Janus Kinase 2, Megakaryocytes, Membrane Proteins, Mutation, Myeloproliferative Disorders, RNA, Single-Cell Analysis, Clone Cells

Published Open-Access

yes

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