Identification of master regulator genes controlling pathogenic CD4+ T cell fate in inflammatory bowel disease through transcriptional network analysis

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dc.contributor.authorJiménez, José M.
dc.contributor.authorContreras-Riquelme, J. Sebastián
dc.contributor.authorVidal, Pía M.
dc.contributor.authorPrado, Carolina
dc.contributor.authorBastías, Macarena
dc.contributor.authorMeneses, Claudio
dc.contributor.authorMartín, Alberto J. M.
dc.contributor.authorPerez-Acle, Tomás
dc.contributor.authorPacheco, Rodrigo
dc.date.accessioned2024-11-14T19:34:43Z
dc.date.available2024-11-14T19:34:43Z
dc.date.issued2024-12
dc.descriptionIndexación: Scopus.
dc.description.abstractInflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune response. Effector CD4+ T cells and regulatory CD4+ T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4+ T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4+ T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1−/− mice received the transfer of the whole CD4+ T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4+ T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4+ T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD. © The Author(s) 2024.
dc.description.urihttps://www-nature-com.recursosbiblioteca.unab.cl/articles/s41598-024-61158-4
dc.identifier.doi10.1038/s41598-024-61158-4
dc.identifier.issn2045-2322
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/62011
dc.language.isoen
dc.publisherScientific Reports, Volume 14, Issue 1 December 2024 Article number 10553
dc.rights.licenseAttribution 4.0 International CC BY 4.0 Deed
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectCD4-Positive T-Lymphocytes
dc.subjectDisease Models, Animal
dc.subjectGene Expression Regulation
dc.subjectGene Regulatory Networks
dc.subjectInflammatory Bowel Diseases
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectT-Lymphocytes, Regulatory
dc.titleIdentification of master regulator genes controlling pathogenic CD4+ T cell fate in inflammatory bowel disease through transcriptional network analysis
dc.typeArtículo
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