Community Detection in a Weighted Directed Hypergraph Representation of Cell-to-cell Communication Networks

Cell-to-cell communication is mainly triggered by ligand-receptor activities. Through ligandreceptor pairs, cells coordinate complex processes such as development, homeostasis, and immune response. In this work, we model the ligand-receptor-mediated cell-to-cell communication network as a weighted directed hypergraph. In this mathematical model, collaborating cell types are considered as a node community while the ligand-receptor pairs connecting them are considered a hyperedge community. We first define the community structures in a weighted directed hypergraph and develop an exact community detection method to identify these communities. We then modify approximate community detection algorithms designed for simple graphs to identify the nodes and hyperedges within each community. Application to synthetic hypergraphs with known community structure confirmed that one of the proposed approximate community identification strategies, named HyperCommunity algorithm, can effectively and precisely detect embedded communities. We then applied this strategy to two organism-wide datasets and identified putative community structures. Notably the method identifies non-overlapping edge-communities mediated by different sets of ligand-receptor pairs, however node-communities can overlap.

[1]  Kenta Nakai,et al.  Organism-Level Analysis of Vaccination Reveals Networks of Protection across Tissues , 2017, Cell.

[2]  T Pawson,et al.  SH2 domains, interaction modules and cellular wiring. , 2001, Trends in cell biology.

[3]  N. Turner,et al.  Advances and challenges in targeting FGFR signalling in cancer , 2017, Nature Reviews Cancer.

[4]  Mirjana Efremova,et al.  CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes , 2020, Nature Protocols.

[5]  Daniel A. Skelly,et al.  Single-Cell Transcriptional Profiling Reveals Cellular Diversity and Intercommunication in the Mouse Heart. , 2018, Cell reports.

[6]  R. Klein,et al.  Excitatory Eph receptors and adhesive ephrin ligands. , 2001, Current opinion in cell biology.

[7]  Giorgio Ausiello,et al.  On-Line Algorithms for Satisfiability Problems with Uncertainty , 1997, Theor. Comput. Sci..

[8]  Francisco Jose,et al.  Strong Connectivity in Directed Hypergraphs and its Application to the Atomic Decomposition of Ontologies , 2016 .

[9]  Jean-Loup Guillaume,et al.  Fast unfolding of communities in large networks , 2008, 0803.0476.

[10]  Giorgio Ausiello,et al.  Graph Algorithms for Functional Dependency Manipulation , 1983, JACM.

[11]  J G Flanagan,et al.  The ephrins and Eph receptors in neural development. , 1998, Annual review of neuroscience.

[12]  D. Vestweber,et al.  How leukocytes cross the vascular endothelium , 2015, Nature Reviews Immunology.

[13]  N. Salomonis,et al.  Cross-platform single cell analysis of kidney development shows stromal cells express Gdnf. , 2017, Developmental biology.

[14]  D. Nikolov,et al.  Cell-cell signaling via Eph receptors and ephrins. , 2007, Current opinion in cell biology.

[15]  M. Lenzen,et al.  Scientists’ warning on affluence , 2020, Nature Communications.

[16]  Marco Temperini,et al.  The Organization of Large-Scale Repositories of Learning Objects with Directed Hypergraphs , 2014, ICWL Workshops.

[17]  Antonio Volpentesta,et al.  Hypernetworks in a directed hypergraph , 2008, Eur. J. Oper. Res..

[18]  Evan Bolton,et al.  Database resources of the National Center for Biotechnology Information , 2017, Nucleic Acids Res..

[19]  Marcus von Lossow A min‐max version of Dijkstra's algorithm with application to perturbed optimal control problems , 2007 .

[20]  S. Orkin,et al.  Mapping the Mouse Cell Atlas by Microwell-Seq , 2018, Cell.

[21]  Piero Carninci,et al.  A draft network of ligand–receptor-mediated multicellular signalling in human , 2015, Nature Communications.

[22]  S. Shen-Orr,et al.  Social network architecture of human immune cells unveiled by quantitative proteomics , 2017, Nature Immunology.

[23]  Philippe Soriano,et al.  Inhibition of Gap Junction Communication at Ectopic Eph/ephrin Boundaries Underlies Craniofrontonasal Syndrome , 2006, PLoS biology.

[24]  Gregory D. Schuler,et al.  Database resources of the National Center for Biotechnology Information: update , 2004, Nucleic acids research.

[25]  J. Schlessinger,et al.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[26]  Jirí Síma,et al.  On the NP-Completeness of Some Graph Cluster Measures , 2005, SOFSEM.

[27]  Rui Hou,et al.  Predicting cell-to-cell communication networks using NATMI , 2020, Nature Communications.

[28]  Kerstin B. Meyer,et al.  Single-cell reconstruction of the early maternal–fetal interface in humans , 2018, Nature.

[29]  Jack A Roth,et al.  MDA-7/IL-24 is a unique cytokine--tumor suppressor in the IL-10 family. , 2004, International immunopharmacology.

[30]  Rahul Tripathi,et al.  Linear connectivity problems in directed hypergraphs , 2009, Theor. Comput. Sci..

[31]  Cesare Furlanello,et al.  A promoter-level mammalian expression atlas , 2015 .

[32]  Emma Gordon,et al.  Mechanisms and regulation of endothelial VEGF receptor signalling , 2016, Nature Reviews Molecular Cell Biology.

[33]  Uri Alon,et al.  Circuit Design Features of a Stable Two-Cell System , 2018, Cell.

[34]  Giorgio Ausiello,et al.  Minimal Representation of Directed Hypergraphs , 1986, SIAM J. Comput..

[35]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[36]  N. Patel,et al.  Unraveling the Tangled Skein: The Evolution of Transcriptional Regulatory Networks in Development. , 2015, Annual review of genomics and human genetics.

[37]  Antonio Brogi,et al.  Semantics-based composition-oriented discovery of Web services , 2008, TOIT.

[38]  J. Schlessinger Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[39]  Dan Zhang,et al.  Construction of a human cell landscape at single-cell level , 2020, Nature.

[40]  O. Gustafsson,et al.  Towards optimal multiple constant multiplication: A hypergraph approach , 2008, 2008 42nd Asilomar Conference on Signals, Systems and Computers.

[41]  Scott A. Smolka,et al.  Simple Linear-Time Algorithms for Minimal Fixed Points (Extended Abstract) , 1998, ICALP.

[42]  Ralf J. Sommer,et al.  The evolution of signalling pathways in animal development , 2003, Nature Reviews Genetics.

[43]  S. Dongen Graph clustering by flow simulation , 2000 .

[44]  Elena B Pasquale,et al.  Eph-Ephrin Bidirectional Signaling in Physiology and Disease , 2008, Cell.

[45]  Elena B. Pasquale,et al.  Developmental cell biology: Eph receptor signalling casts a wide net on cell behaviour , 2005, Nature Reviews Molecular Cell Biology.

[46]  Rui Wang,et al.  Software architecture construction and collaboration based on service dependency , 2015, 2015 IEEE 19th International Conference on Computer Supported Cooperative Work in Design (CSCWD).

[47]  T. Hunter,et al.  Signaling—2000 and Beyond , 2000, Cell.

[48]  Koki Tsuyuzaki,et al.  Uncovering hypergraphs of cell-cell interaction from single cell RNA-sequencing data , 2019, bioRxiv.

[49]  Daniele Pretolani,et al.  A directed hypergraph model for random time dependent shortest paths , 2000, Eur. J. Oper. Res..

[50]  Emmanuel Tsukerman Tropical Spectral Theory of Tensors , 2014, ArXiv.

[51]  P. Reddien,et al.  Fundamentals of planarian regeneration. , 2004, Annual review of cell and developmental biology.