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JAK-STAT Pathway Inhibition Partially Restores Intestinal Homeostasis in Hdac1- and Hdac2-Intestinal Epithelial Cell-Deficient Mice

Département D’immunologie et Biologie Cellulaire, Pavillon de Recherche Appliquée Sur le Cancer, Faculté de Médecine et Des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
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Cells 2021, 10(2), 224; https://doi.org/10.3390/cells10020224
Received: 23 November 2020 / Revised: 18 January 2021 / Accepted: 19 January 2021 / Published: 23 January 2021
We have previously reported that histone deacetylase epigenetic regulator Hdac1 and Hdac2 deletion in intestinal epithelial cells (IEC) disrupts mucosal tissue architecture and barrier, causing chronic inflammation. In this study, proteome and transcriptome analysis revealed the importance of signaling pathways induced upon genetic IEC-Hdac1 and Hdac2 deletion. Indeed, Gene Ontology biological process analysis of enriched deficient IEC RNA and proteins identified common pathways, including lipid metabolic and oxidation–reduction process, cell adhesion, and antigen processing and presentation, related to immune responses, correlating with dysregulation of major histocompatibility complex (MHC) class II genes. Top upstream regulators included regulators associated with environmental sensing pathways to xenobiotics, microbial and diet-derived ligands, and endogenous metabolites. Proteome analysis revealed mTOR signaling IEC-specific defects. In addition to mTOR, the STAT and Notch pathways were dysregulated specifically in jejunal IEC. To determine the impact of pathway dysregulation on mutant jejunum alterations, we treated mutant mice with Tofacitinib, a JAK inhibitor. Treatment with the inhibitor partially corrected proliferation and tight junction defects, as well as niche stabilization by increasing Paneth cell numbers. Thus, IEC-specific histone deacetylases 1 (HDAC1) and 2 (HDAC2) support intestinal homeostasis by regulating survival and translation processes, as well as differentiation and metabolic pathways. HDAC1 and HDAC2 may play an important role in the regulation of IEC-specific inflammatory responses by controlling, directly or indirectly, the JAK/STAT pathway. IEC-specific JAK/STAT pathway deregulation may be, at least in part, responsible for intestinal homeostasis disruption in mutant mice. View Full-Text
Keywords: intestinal epithelial cell; HDAC; proteome; transcriptome; organoid; STAT3; tofacitinib intestinal epithelial cell; HDAC; proteome; transcriptome; organoid; STAT3; tofacitinib
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MDPI and ACS Style

Gonneaud, A.; Turgeon, N.; Boisvert, F.-M.; Boudreau, F.; Asselin, C. JAK-STAT Pathway Inhibition Partially Restores Intestinal Homeostasis in Hdac1- and Hdac2-Intestinal Epithelial Cell-Deficient Mice. Cells 2021, 10, 224. https://doi.org/10.3390/cells10020224

AMA Style

Gonneaud A, Turgeon N, Boisvert F-M, Boudreau F, Asselin C. JAK-STAT Pathway Inhibition Partially Restores Intestinal Homeostasis in Hdac1- and Hdac2-Intestinal Epithelial Cell-Deficient Mice. Cells. 2021; 10(2):224. https://doi.org/10.3390/cells10020224

Chicago/Turabian Style

Gonneaud, Alexis; Turgeon, Naomie; Boisvert, Francois-Michel; Boudreau, Francois; Asselin, Claude. 2021. "JAK-STAT Pathway Inhibition Partially Restores Intestinal Homeostasis in Hdac1- and Hdac2-Intestinal Epithelial Cell-Deficient Mice" Cells 10, no. 2: 224. https://doi.org/10.3390/cells10020224

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