Gene regulatory network underlying the immortalization of epithelial cells
Abstract Background: Tumorigenic transformationofhumanepithelialcellsinvitrohasbeendescribedexperimentallyas thepotentialresultofspontaneousimmortalization.Thisprocessischaracterizedbyaseriesofcell–statetransitions,in whichnormalepithelialcellsacquirefirstasenescentstatewhichislatersurpassedtoattain...
| Autores principales: | , , , , , |
|---|---|
| Formato: | Artículo |
| Lenguaje: | inglés |
| Publicado: |
2017
|
| Materias: | |
| Acceso en línea: | http://eprints.uanl.mx/18138/1/436.pdf |
| _version_ | 1824415144965308416 |
|---|---|
| author | Méndez López, Luis Fernando Dávila Velderrain, José Domínguez Hüttinger, Elisa Enríquez Olguín, Christian Martínez García, Juan Carlos Alvarez Buylla Roces, María Elena |
| author_facet | Méndez López, Luis Fernando Dávila Velderrain, José Domínguez Hüttinger, Elisa Enríquez Olguín, Christian Martínez García, Juan Carlos Alvarez Buylla Roces, María Elena |
| author_sort | Méndez López, Luis Fernando |
| collection | Repositorio Institucional |
| description | 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 |
| format | Article |
| id | eprints-18138 |
| institution | UANL |
| language | English |
| publishDate | 2017 |
| record_format | eprints |
| spelling | eprints-181382024-03-05T18:46:14Z http://eprints.uanl.mx/18138/ Gene regulatory network underlying the immortalization of epithelial cells Méndez López, Luis Fernando Dávila Velderrain, José Domínguez Hüttinger, Elisa Enríquez Olguín, Christian Martínez García, Juan Carlos Alvarez Buylla Roces, María Elena QH Historia Natural, Biología 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 2017 Article PeerReviewed text en cc_by_nc_nd http://eprints.uanl.mx/18138/1/436.pdf http://eprints.uanl.mx/18138/1.haspreviewThumbnailVersion/436.pdf Méndez López, Luis Fernando y Dávila Velderrain, José y Domínguez Hüttinger, Elisa y Enríquez Olguín, Christian y Martínez García, Juan Carlos y Alvarez 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 http://doi.org/10.1186/s12918-017-0393-5 doi:10.1186/s12918-017-0393-5 |
| spellingShingle | QH Historia Natural, Biología Méndez López, Luis Fernando Dávila Velderrain, José Domínguez Hüttinger, Elisa Enríquez Olguín, Christian Martínez García, Juan Carlos Alvarez Buylla Roces, María Elena Gene regulatory network underlying the immortalization of epithelial cells |
| thumbnail | https://rediab.uanl.mx/themes/sandal5/images/online.png |
| title | Gene regulatory network underlying the immortalization of epithelial cells |
| title_full | Gene regulatory network underlying the immortalization of epithelial cells |
| title_fullStr | Gene regulatory network underlying the immortalization of epithelial cells |
| title_full_unstemmed | Gene regulatory network underlying the immortalization of epithelial cells |
| title_short | Gene regulatory network underlying the immortalization of epithelial cells |
| title_sort | gene regulatory network underlying the immortalization of epithelial cells |
| topic | QH Historia Natural, Biología |
| url | http://eprints.uanl.mx/18138/1/436.pdf |
| work_keys_str_mv | AT mendezlopezluisfernando generegulatorynetworkunderlyingtheimmortalizationofepithelialcells AT davilavelderrainjose generegulatorynetworkunderlyingtheimmortalizationofepithelialcells AT dominguezhuttingerelisa generegulatorynetworkunderlyingtheimmortalizationofepithelialcells AT enriquezolguinchristian generegulatorynetworkunderlyingtheimmortalizationofepithelialcells AT martinezgarciajuancarlos generegulatorynetworkunderlyingtheimmortalizationofepithelialcells AT alvarezbuyllarocesmariaelena generegulatorynetworkunderlyingtheimmortalizationofepithelialcells |