Pseudocell Tracer-A method for inferring dynamic trajectories using scRNAseq and its application to B cells undergoing immunoglobulin class switch recombination.

Journal: PLoS computational biology
PMID: 33939691

Abstract

Single cell RNA sequencing (scRNAseq) can be used to infer a temporal ordering of cellular states. Current methods for the inference of cellular trajectories rely on unbiased dimensionality reduction techniques. However, such biologically agnostic ordering can prove difficult for modeling complex developmental or differentiation processes. The cellular heterogeneity of dynamic biological compartments can result in sparse sampling of key intermediate cell states. To overcome these limitations, we develop a supervised machine learning framework, called Pseudocell Tracer, which infers trajectories in pseudospace rather than in pseudotime. The method uses a supervised encoder, trained with adjacent biological information, to project scRNAseq data into a low-dimensional manifold that maps the transcriptional states a cell can occupy. Then a generative adversarial network (GAN) is used to simulate pesudocells at regular intervals along a virtual cell-state axis. We demonstrate the utility of Pseudocell Tracer by modeling B cells undergoing immunoglobulin class switch recombination (CSR) during a prototypic antigen-induced antibody response. Our results revealed an ordering of key transcription factors regulating CSR to the IgG1 isotype, including the concomitant expression of Nfkb1 and Stat6 prior to the upregulation of Bach2 expression. Furthermore, the expression dynamics of genes encoding cytokine receptors suggest a poised IL-4 signaling state that preceeds CSR to the IgG1 isotype.

Authors

  • Derek Reiman
  • Godhev Kumar Manakkat Vijay
    University of Pittsburgh, Center for Systems Immunology, Departments of Immunology and Computational and Systems Biology, Pittsburgh, Pennsylvania, United States of America.
  • Heping Xu
    Department of Medical Physics, Walker Family Cancer Centre, St. Catharines, ON, Canada.
  • Andrew Sonin
    Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia.
  • Dianyu Chen
    Key Laboratory of Growth Regulation and Translation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
  • Nathan Salomonis
    Department of Pediatrics, Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, 3333 Burnet Avenue, MLC 7024, Cincinnati, OH, 45229, USA. nathan.salomonis@cchmc.org.
  • Harinder Singh
    University of Pittsburgh, Center for Systems Immunology, Departments of Immunology and Computational and Systems Biology, Pittsburgh, Pennsylvania, United States of America.
  • Aly A Khan
    Toyota Technological Institute at Chicago, Chicago, IL, USA.

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