Gene regulatory network underlying the immortalization of epithelial cells

Méndez López, Luis Fernando y Davila Velderrain, José y Domínguez Hüttinger, Elisa y Enríquez Olguín, Christian y Martínez García, Juan Carlos y Álvarez-Buylla Roces, María Elena (2017) Gene regulatory network underlying the immortalization of epithelial cells. BMC Systems Biology, 11 (1). pp. 1-15. ISSN 1752-0509

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Abstract Background: Tumorigenic transformationofhumanepithelialcellsinvitrohasbeendescribedexperimentallyas thepotentialresultofspontaneousimmortalization.Thisprocessischaracterizedbyaseriesofcell–statetransitions,in whichnormalepithelialcellsacquirefirstasenescentstatewhichislatersurpassedtoattainamesenchymalstem–like phenotypewithapotentiallytumorigenicbehavior.Inthispaperweaimtoprovideasystem–levelmechanistic explanationtotheemergenceofthesecelltypes,andtothetime–orderedtransitionpatternsthatarecommonto neoplasiasofepithelialorigin.Tothisend,wefirstintegratepublishedfunctionalandwell–curatedmoleculardataof thecomponentsandinteractionsthathavebeenfoundtobeinvolvedinsuchcellstatesandtransitionsintoa networkof41molecularcomponents.Wethenreducethisinitialnetworkbyremovingsimplemediators(i.e.,linear pathways),andformalizetheresultingregulatorycoreintologicalrulesthatgovernthedynamicsofeachofthe networkcomponentsasafunctionofthestatesofitsregulators. Results: ComputationaldynamicanalysisshowsthatourproposedGeneRegulatoryNetworkmodelrecoversexactly threeattractors,eachofthemdefinedbyaspecificgeneexpressionprofilethatcorrespondstotheepithelial, senescent,andmesenchymalstem–likecellularphenotypes,respectively.Weshowthatalthoughamesenchymal stem–likestatecanbeattainedevenunderunperturbedphysiologicalconditions,thelikelihoodofconvergingtothis stateisincreasedwhenpro–inflammatoryconditionsaresimulated,providingasystems–levelmechanistic explanationforthecarcinogenicroleofchronicinflammatoryconditionsobservedintheclinic.Wealsofoundthat theregulatorycoreyieldsanepigeneticlandscapethatrestrictstemporalpatternsofprogressionbetweenthesteady states,suchthatrecoveredpatternsresemblethetime–orderedtransitionsobservedduringthespontaneous immortalizationofepithelialcells,bothinvivoandinvitro. Conclusion: Ourstudystronglysuggeststhattheinvitrotumorigenictransformationofepithelialcells,which stronglycorrelateswiththepatternsobservedduringthepathologicalprogressionofepithelialcarcinogenesisinvivo, emergesfromunderlyingregulatorynetworksinvolvedinepithelialtrans–differentiationduringdevelopment. Keywords: Carcinomas,Generegulatorynetworks,Epigeneticlandscape,Booleanmodels,Phenotypicattractors

Tipo de elemento: Article
Palabras claves no controlados: Carcinomas, Gene regulatory networks, Epigenetic landscape, Boolean models, Phenotypic attractors
Materias: Q Ciencia > QH Historia Natural, Biología
Divisiones: Ciencias Biológicas
Usuario depositante: Editor Repositorio
Creadores:
CreadorEmailORCID
Méndez López, Luis FernandoNO ESPECIFICADONO ESPECIFICADO
Davila Velderrain, JoséNO ESPECIFICADONO ESPECIFICADO
Domínguez Hüttinger, ElisaNO ESPECIFICADONO ESPECIFICADO
Enríquez Olguín, ChristianNO ESPECIFICADONO ESPECIFICADO
Martínez García, Juan CarlosNO ESPECIFICADONO ESPECIFICADO
Álvarez-Buylla Roces, María ElenaNO ESPECIFICADONO ESPECIFICADO
Fecha del depósito: 18 Mar 2020 18:31
Última modificación: 30 Abr 2020 17:56
URI: http://eprints.uanl.mx/id/eprint/18138

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