Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths Journal Article

   

Authors:	Cortés-López, M.; Chamely, P.; Hawkins, A. G.; Stanley, R. F.; Swett, A. D.; Ganesan, S.; Mouhieddine, T. H.; Dai, X.; Kluegel, L.; Chen, C.; Batta, K.; Furer, N.; Vedula, R. S.; Beaulaurier, J.; Drong, A. W.; Hickey, S.; Dusaj, N.; Mullokandov, G.; Stasiw, A. M.; Su, J.; Chaligné, R.; Juul, S.; Harrington, E.; Knowles, D. A.; Potenski, C. J.; Wiseman, D. H.; Tanay, A.; Shlush, L.; Lindsley, R. C.; Ghobrial, I. M.; Taylor, J.; Abdel-Wahab, O.; Gaiti, F.; Landau, D. A.
Article Title:	Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths
Abstract:	RNA splicing factors are recurrently mutated in clonal blood disorders, but the impact of dysregulated splicing in hematopoiesis remains unclear. To overcome technical limitations, we integrated genotyping of transcriptomes (GoT) with long-read single-cell transcriptomics and proteogenomics for single-cell profiling of transcriptomes, surface proteins, somatic mutations, and RNA splicing (GoT-Splice). We applied GoT-Splice to hematopoietic progenitors from myelodysplastic syndrome (MDS) patients with mutations in the core splicing factor SF3B1. SF3B1mut cells were enriched in the megakaryocytic-erythroid lineage, with expansion of SF3B1mut erythroid progenitor cells. We uncovered distinct cryptic 3′ splice site usage in different progenitor populations and stage-specific aberrant splicing during erythroid differentiation. Profiling SF3B1-mutated clonal hematopoiesis samples revealed that erythroid bias and cell-type-specific cryptic 3′ splice site usage in SF3B1mut cells precede overt MDS. Collectively, GoT-Splice defines the cell-type-specific impact of somatic mutations on RNA splicing, from early clonal outgrowths to overt neoplasia, directly in human samples. © 2023 Elsevier Inc.
Keywords:	genetics; mutation; metabolism; myelodysplastic syndrome; phosphoproteins; phosphoprotein; rna splicing; myelodysplastic syndromes; splicing; rna splice sites; bax; genotyping; rna-seq; single cell; clonal hematopoiesis; humans; human; sf3b1; rna splicing factor; rna splicing factors; multi-omics; rna splice site; multiomics; long-read sequencing
Journal Title:	Cell Stem Cell
Volume:	30
Issue:	9
ISSN:	1934-5909
Publisher:	Cell Press
Date Published:	2023-09-07
Start Page:	1262
End Page:	1281.e8
Language:	English
DOI:	10.1016/j.stem.2023.07.012
PUBMED:	37582363
PROVIDER:	scopus
PMCID:	PMC10528176
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85169010948&doi=10.1016%2fj.stem.2023.07.012&partnerID=40&md5=5102c1e4c99e475fde30809756283d5e
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/209835