Clonal multi-omics reveals Bcor as a negative regulator of emergency dendritic cell development

Luyi Tian, Sara Tomei, Jaring Schreuder, Tom S. Weber, Daniela Amann-Zalcenstein, Dawn S. Lin, Jessica Tran, Cindy Audiger, Mathew Chu, Andrew Jarratt, Tracy Willson, Adrienne Hilton, Ee Shan Pang, Timothy Patton, Madison Kelly, Shian Su, Quentin Gouil, Peter Diakumis, Melanie Bahlo, Toby SargeantLev M. Kats, Philip D. Hodgkin, Meredith O'Keeffe, Ashley P. Ng, Matthew E. Ritchie, Shalin H. Naik

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4 Citations (Scopus)

Abstract

Despite advances in single-cell multi-omics, a single stem or progenitor cell can only be tested once. We developed clonal multi-omics, in which daughters of a clone act as surrogates of the founder, thereby allowing multiple independent assays per clone. With SIS-seq, clonal siblings in parallel “sister” assays are examined either for gene expression by RNA sequencing (RNA-seq) or for fate in culture. We identified, and then validated using CRISPR, genes that controlled fate bias for different dendritic cell (DC) subtypes. This included Bcor as a suppressor of plasmacytoid DC (pDC) and conventional DC type 2 (cDC2) numbers during Flt3 ligand-mediated emergency DC development. We then developed SIS-skew to examine development of wild-type and Bcor-deficient siblings of the same clone in parallel. We found Bcor restricted clonal expansion, especially for cDC2s, and suppressed clonal fate potential, especially for pDCs. Therefore, SIS-seq and SIS-skew can reveal the molecular and cellular mechanisms governing clonal fate.

Original languageEnglish
Pages (from-to)1338-1351.e9
Number of pages24
JournalImmunity
Volume54
Issue number6
DOIs
Publication statusPublished - 8 Jun 2021

Keywords

  • cellular barcoding
  • clonal lineage tracing
  • CRISPR minipool
  • dendritic cell
  • Flt3 ligand
  • immunotherapy
  • single-cell fate
  • single-cell RNA-seq
  • state-fate

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