title: Computational integration of homolog and pathway gene module expression reveals general stemness signatures.
abstract: The stemness hypothesis states that all stem cells use common mechanisms to regulate self-renewal and multi-lineage potential. However, gene expression meta-analyses at the single gene level have failed to identify a significant number of genes selectively expressed by a broad range of stem cell types. We hypothesized that stemness may be regulated by modules of homologs. While the expression of any single gene within a module may vary from one stem cell type to the next, it is possible that the expression of the module as a whole is required so that the expression of different, yet functionally-synonymous, homologs is needed in different stem cells. Thus, we developed a computational method to test for stem cell-specific gene expression patterns from a comprehensive collection of 49 murine datasets covering 12 different stem cell types. We identified 40 individual genes and 224 stemness modules with reproducible and specific up-regulation across multiple stem cell types. The stemness modules included families regulating chromatin remodeling, DNA repair, and Wnt signaling. Strikingly, the majority of modules represent evolutionarily related homologs. Moreover, a score based on the discovered modules could accurately distinguish stem cell-like populations from other cell types in both normal and cancer tissues. This scoring system revealed that both mouse and human metastatic populations exhibit higher stemness indices than non-metastatic populations, providing further evidence for a stem cell-driven component underlying the transformation to metastatic disease.
authors.affiliation: Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.
authors.forename: Martina
authors.initials: M
authors.lastname: Koeva
authors.forename: E Camilla
authors.initials: EC
authors.lastname: Forsberg
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
mesh_terms: D000465:Algorithms; D000818:Animals; D002843:Chromatin / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D004260:DNA Repair; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008954:Models, Biological; D015233:Models, Statistical; D009369:Neoplasms / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D002843:Chromatin; D051153:Wnt Proteins