Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

Alenghat, Theresa, Osborne, Lisa C., Saenz, Steven A., Kobuley, Dmytro, Ziegler, Carly G.K., Mullican, Shannon E., Choi, Inchan, Grunberg, Stephanie, Sinha, Rohini, Wynosky-Dolfi, Meghan, Snyder, Annelise, Giacomin, Paul R., Joyce, Karen L., Hoang, Tram B., Bewtra, Meenakshi, Brodsky, Igor E., Sonnenberg, Gregory F., Bushman, Frederic D., Won, Kyoung-Jae, Lazar, Mitchell A., and Artis, David (2013) Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature, 504. pp. 153-157.

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Abstract

The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3(ΔIEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(ΔIEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(ΔIEC) mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3(ΔIEC) mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.

Item ID: 30108
Item Type: Article (Research - C1)
ISSN: 1476-4687
Additional Information:

PDF contains article plus 12 pages of supporting material.

Date Deposited: 06 Dec 2013 01:36
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110801 Medical Bacteriology @ 25%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110707 Innate Immunity @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110307 Gastroenterology and Hepatology @ 25%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 50%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920105 Digestive System Disorders @ 50%
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