title: Dissecting the calcium-induced differentiation of human primary keratinocytes stem cells by integrative and structural network analyses.
abstract: The molecular details underlying the time-dependent assembly of protein complexes in cellular networks, such as those that occur during differentiation, are largely unexplored. Focusing on the calcium-induced differentiation of primary human keratinocytes as a model system for a major cellular reorganization process, we look at the expression of genes whose products are involved in manually-annotated protein complexes. Clustering analyses revealed only moderate co-expression of functionally related proteins during differentiation. However, when we looked at protein complexes, we found that the majority (55%) are composed of non-dynamic and dynamic gene products ('di-chromatic'), 19% are non-dynamic, and 26% only dynamic. Considering three-dimensional protein structures to predict steric interactions, we found that proteins encoded by dynamic genes frequently interact with a common non-dynamic protein in a mutually exclusive fashion. This suggests that during differentiation, complex assemblies may also change through variation in the abundance of proteins that compete for binding to common proteins as found in some cases for paralogous proteins. Considering the example of the TNF-α/NFκB signaling complex, we suggest that the same core complex can guide signals into diverse context-specific outputs by addition of time specific expressed subunits, while keeping other cellular functions constant. Thus, our analysis provides evidence that complex assembly with stable core components and competition could contribute to cell differentiation.
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Kiana
authors.initials: K
authors.lastname: Toufighi
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Jae-Seong
authors.initials: JS
authors.lastname: Yang
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Nuno Miguel
authors.initials: NM
authors.lastname: Luis
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Institute for Research in Biomedicine, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Aznar Benitah
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
authors.forename: Ben
authors.initials: B
authors.lastname: Lehner
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Christina
authors.initials: C
authors.lastname: Kiel
mesh_terms: D002118:Calcium / Q000737:chemistry*; D002454:Cell Differentiation; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D000078404:Epidermal Cells; D020869:Gene Expression Profiling; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D015233:Models, Statistical; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025941:Protein Interaction Mapping; D015398:Signal Transduction; D012984:Software; D013234:Stem Cells / Q000166:cytology*; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium