title: The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis.
abstract: Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from dextran sulfate sodium (DSS)-induced murine colitis. Although tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal disease activity index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability, and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation.
authors: Département d'anatomie et biologie cellulaire, Faculté de médecine et des sciences de la santé, Pavillon de recherche appliquée sur le cancer, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Naomie
authors: N
authors: Turgeon
authors: Julie Moore
authors: JM
authors: Gagné
authors: Mylène
authors: M
authors: Blais
authors: Fernand-Pierre
authors: FP
authors: Gendron
authors: François
authors: F
authors: Boudreau
authors: Claude
authors: C
authors: Asselin
mesh_terms: D000818:Animals; D003092:Colitis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D005838:Genotype; D056284:Histone Deacetylase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D010641:Phenotype; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators; D016264:Dextran Sulfate; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: DSS; Hdac1; Hdac2; colitis; inflammation; intestinal epithelial cell