PHLOWER - Single cell trajectory analysis using Hodge Decomposition

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

ABSTRACT Multi-modal single-cell sequencing, which captures changes in chromatin and gene expression in the same cells, is a game changer in the study of gene regulation in cellular differentiation processes. Computational trajectory analysis is a key computational task for inferring differentiation trees from this single-cell data, though current methods struggle with complex, multi-branching trees and multi-modal data. To address this, PHLOWER (decomPosition of the Hodge Laplacian for inferring trajectOries from floWs of cEll diffeRentiation) leverages the harmonic component of the Hodge decomposition on simplicial complexes to infer trajectory embeddings. These natural representations of cell differentiation facilitate the estimation of their underlying differentiation trees. We evaluate PHLOWER through benchmarking with multi-branching differentiation trees and using novel kidney organoid multi-modal and spatial single-cell data. These demonstrate the power of PHLOWER in both the inference of complex trees and the identification of transcription factors regulating off-target cells in kidney organoids.

Authors 11

1. Mingbo Cheng Aachen Institute for Computational Genomics Joint Research Centre for Computational Biomedicine (JRC-COMBINE)

   RWTH Aachen University

   Affiliation as printed

   Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University Medical School, 52074 Aachen, Germany

2. Jitske Jansen Aachen Division of Nephrology and Clinical Immunology Institute of Experimental Medicine and Systems Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52062 Aachen, Germany

   Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 52062 Aachen, Germany

3. Katharina C. Reimer Aachen Division of Nephrology and Clinical Immunology Institute of Experimental Medicine and Systems Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52062 Aachen, Germany

   Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 52062 Aachen, Germany

4. James Shiniti Nagai Aachen Institute for Computational Genomics Joint Research Centre for Computational Biomedicine (JRC-COMBINE)

   RWTH Aachen University

   Affiliation as printed

   Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University Medical School, 52074 Aachen, Germany

5. Zhijian Li

   Broad Institute · Massachusetts General Hospital · Massachusetts Institute of Technology

   Affiliation as printed

   Gene Regulation Observatory, The Broad Institute of Harvard and MIT, Cambridge, MA, USA

   Molecular Pathology Unit, Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA

6. Paul Kießling Aachen Institute of Experimental Medicine and Systems Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 52062 Aachen, Germany

7. Martin Graßhoff Aachen Institute for Computational Genomics Joint Research Centre for Computational Biomedicine (JRC-COMBINE)

   RWTH Aachen University

   Affiliation as printed

   Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University Medical School, 52074 Aachen, Germany

8. Christoph Kuppe Aachen Division of Nephrology and Clinical Immunology Institute of Experimental Medicine and Systems Biology

   RWTH Aachen University

   Affiliation as printed

   Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52062 Aachen, Germany

   Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 52062 Aachen, Germany

9. Michael T. Schaub Aachen Department of Computer Science

   RWTH Aachen University

   Affiliation as printed

   Department of Computer Science, RWTH Aachen University, 52074 Aachen, Germany

10. Rafael Kramann Aachen Division of Nephrology and Clinical Immunology Institute of Experimental Medicine and Systems Biology

    Erasmus MC · RWTH Aachen University

    Affiliation as printed

    Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands

    Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52062 Aachen, Germany

    Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, 52062 Aachen, Germany

11. Ivan G. Costa corresponding Aachen Institute for Computational Genomics Joint Research Centre for Computational Biomedicine (JRC-COMBINE)

    RWTH Aachen University

    Affiliation as printed

    Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University Medical School, 52074 Aachen, Germany