title: A multi-scale approach reveals that NF-κB cRel enforces a B-cell decision to divide.
abstract: Understanding the functions of multi-cellular organs in terms of the molecular networks within each cell is an important step in the quest to predict phenotype from genotype. B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically. Based on tracking single-cell time-lapse trajectories of hundreds of B cells, single-cell transcriptome, and immunofluorescence analyses, we constructed an agent-based multi-modular computational model to simulate lymphocyte population dynamics in terms of the molecular networks that control NF-κB signaling, the cell cycle, and apoptosis. Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells. But as cRel deficiency causes growing B cells to die at similar rates to non-growing cells, our analysis reveals that the phenomenological decision model of wild-type cells is rooted in a biased race of cell fates. We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.
authors: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.
authors: Maxim N
authors: MN
authors: Shokhirev
authors: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA Biological Sciences Graduate Program, UCSD, La Jolla, CA, USA.
authors: Jonathan
authors: J
authors: Almaden
authors: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.
authors: Jeremy
authors: J
authors: Davis-Turak
authors: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Institute for Quantitative and Computational Biosciences, Los Angeles, CA, USA Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA.
authors: Harry A
authors: HA
authors: Birnbaum
authors: Fluidigm Corporation, South San Francisco, CA, USA.
authors: Theresa M
authors: TM
authors: Russell
authors: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Institute for Quantitative and Computational Biosciences, Los Angeles, CA, USA Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA.
authors: Jesse A D
authors: JA
authors: Vargas
authors: Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Institute for Quantitative and Computational Biosciences, Los Angeles, CA, USA Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA ahoffmann@ucla.edu.
authors: Alexander
authors: A
authors: Hoffmann
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002455:Cell Division; D049109:Cell Proliferation; D051379:Mice; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology
chemical_list: D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel
keywords: B‐lymphocyte; NF‐κB cRel; apoptosis; cell cycle; cell fate decision