title: Distinct Roles for Intestinal Epithelial Cell-Specific Hdac1 and Hdac2 in the Regulation of Murine Intestinal Homeostasis.
abstract: The intestinal epithelium responds to and transmits signals from the microbiota and the mucosal immune system to insure intestinal homeostasis. These interactions are in part conveyed by epigenetic modifications, which respond to environmental changes. Protein acetylation is an epigenetic signal regulated by histone deacetylases, including Hdac1 and Hdac2. We have previously shown that villin-Cre-inducible intestinal epithelial cell (IEC)-specific Hdac1 and Hdac2 deletions disturb intestinal homeostasis. To determine the role of Hdac1 and Hdac2 in the regulation of IEC function and the establishment of the dual knockout phenotype, we have generated villin-Cre murine models expressing one Hdac1 allele without Hdac2, or one Hdac2 allele without Hdac1. We have also investigated the effect of short-term deletion of both genes in naphtoflavone-inducible Ah-Cre and tamoxifen-inducible villin-Cre(ER) mice. Mice with one Hdac1 allele displayed normal tissue architecture, but increased sensitivity to DSS-induced colitis. In contrast, mice with one Hdac2 allele displayed intestinal architecture defects, increased proliferation, decreased goblet cell numbers as opposed to Paneth cells, increased immune cell infiltration associated with fibrosis, and increased sensitivity to DSS-induced colitis. In comparison to dual knockout mice, intermediary activation of Notch, mTOR, and Stat3 signaling pathways was observed. While villin-Cre(ER) Hdac1 and Hdac2 deletions led to an impaired epithelium and differentiation defects, Ah-Cre-mediated deletion resulted in blunted proliferation associated with the induction of a DNA damage response. Our results suggest that IEC determination and intestinal homeostasis are highly dependent on Hdac1 and Hdac2 activity levels, and that changes in the IEC acetylome may alter the mucosal environment.
authors.affiliation: Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Alexis
authors.initials: A
authors.lastname: Gonneaud
authors.affiliation: Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Naomie
authors.initials: N
authors.lastname: Turgeon
authors.affiliation: Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Boudreau
authors.affiliation: Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Perreault
authors.affiliation: Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rivard
authors.affiliation: Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Asselin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D003092:Colitis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004249:DNA Damage; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology; D020397:Goblet Cells / Q000166:cytology / Q000201:enzymology; 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; D007413:Intestinal Mucosa / Q000002:abnormalities / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051880:Receptors, Notch / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2