Single-cell multi-omics in human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation.

Clonal hematopoiesis (CH) reflects clonal expansion of blood stem and progenitor cells with somatic mutations. We leveraged multi-modality single-cell sequencing to capture mutation status together with the transcriptome and methylome of CD34+ hematopoietic progenitor cells from five individuals with DNMT3A R882-mutated CH. Overall design: We profiled CD34+ enriched cells from GCSF mobilized bone marrow samples (n = 4) using single-cell RNA sequencing (10X) with targeted genotyping, and single-cell DNA methylation (RRBS) with single-cell RNA sequencing (Smart-Seq2) and targeted genotyping. A 5th CH bone marrow aspirate sample was obtained to validate observed results. **Submitter declares that the raw data are being deposited in EGA due to patient privacy concerns**