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. 2013 Dec 5;504(7478):153-7.
doi: 10.1038/nature12687. Epub 2013 Nov 3.

"V体育官网入口" Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

Theresa Alenghat  1 , Lisa C Osborne, Steven A Saenz, Dmytro Kobuley, Carly G K Ziegler, Shannon E Mullican, Inchan Choi, Stephanie Grunberg, Rohini Sinha, Meghan Wynosky-Dolfi, Annelise Snyder, Paul R Giacomin, Karen L Joyce, Tram B Hoang, Meenakshi Bewtra, Igor E Brodsky, Gregory F Sonnenberg, Frederic D Bushman, Kyoung-Jae Won, Mitchell A Lazar, David Artis
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Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis (VSports最新版本)

Theresa Alenghat et al. Nature. .

"VSports app下载" 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 VSports手机版. 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. .

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Figures

Figure 1
Figure 1. Decreased expression of HDAC3 in IECs is associated with global alterations in gene expression and histone acetylation
(a, b) HDAC3 in (a) human and (b) mouse IECs by Western analysis (small (SI) and large (LI) intestine). (c) HDAC3 expression in human colon. No primary antibody (Neg). Bars, 25µm. (d, e) HDAC3 mRNA in IECs from (d) terminal ileum (TI) or (e) LI of control (Con), Crohn’s disease (CD), or ulcerative colitis (UC) patients. *p<0.05, Mann Whitney (TI: 8 Con, 9 CD; LI: 10 Con, 8 UC). (f) Expression heat-map in sorted EpCAM+ IECs from the large intestine of HDAC3FF(FF) versus HDAC3ΔIEC(ΔIEC) mice (fold change > 1.5, row-normalized Z-score). (g) Enriched pathways using DAVID. (h) mRNA in large intestinal IECs. (i) Average profile of H3K9Ac near upregulated genes in HDAC3ΔIEC mice. ***p = 8.64e-44. (j) Representative distribution of H3K9Ac at select genes from (i). (k) Average profile of H3K9Ac near downregulated genes in HDAC3ΔIEC mice. H3K9Ac signals are normalized to reads per 10 million mapped reads. n=3 mice per group. Results are shown as mean ± SEM. *p< 0.05.
Figure 2
Figure 2. IEC-intrinsic HDAC3 expression regulates intestinal homeostasis
(a) PAS/Alcian Blue stained ileal sections. Box surrounds Paneth cells. Bars, 50 µm. (b) Paneth cells per crypt. (c) Immunofluorescent staining of lysozyme (pink) and nuclei (blue). Bars, 10µm. (d) Colonic sections. Bars, 100µm. (e) Crypt length in colon. n = 3 mice per group. (f) Albumin from fecal samples of HDAC3FF (n=8) and HDAC3ΔIEC (n=6) mice. (g) LPS levels in mesenteric lymph node (mLN). n=8 mice per group. (h) Development of rectal prolapse in HDAC3ΔIEC mice (n=13). Data are representative of 2–3 independent experiments. Results are shown as mean ± SEM. *p< 0.05, **p<0.01.
Figure 3
Figure 3. IEC-intrinsic HDAC3 expression regulates susceptibility to DSS-induced intestinal damage and inflammation
(a) Changes in body weight following 2.5% DSS. (b) Total disease score and (c, d) colon length (% naive) on day 5 of DSS. (e) Frequencies of neutrophils (CD11b+ Ly6G+) and macrophages (CD11b+ Ly6G−) in the colonic lamina propria. (f) Intestinal sections (Cecum: top; Colon: bottom; inset: 40x of crypt abscess). (g) Changes in body weight for tamoxifen-induced mice. (h) Total disease score on day 5 of DSS. Data are representative of four independent experiments containing 4 mice per group. (i) Comparison of stool bacterial communities at multiple timepoints (red circles: 6 weeks, blue squares: 8 weeks, orange triangle: 10 weeks). (j) Phylum comparison of compiled samples from (i). (k, l) Average UniFrac distance between HDAC3FF and HDAC3ΔIEC mice (FF-ΔIEC) or within genotypes (FF-FF or ΔIEC-ΔIEC) based on 16S rRNA gene sequences from (k) small or (l) large intestinal luminal samples. n=3 mice per group. (m, n) Changes in body weight of mice (m) cross-fostered(CF) or (n) co-housed(CH) with HDAC3FF or HDAC3ΔIEC mice prior to DSS treatment. (o) Changes in body weight following DSS and (p) ileal sections from colonized germ-free (GF) mice. Data are representative of 2–3 independent experiments containing 3 mice per group. Bars, 50µm. Results are shown as mean ± SEM *p<0.05, **p<0.01.
Figure 4
Figure 4. HDAC3-dependent regulation of intestinal homeostasis depends on integration of commensal bacteria-derived signals
(a) Venn diagram showing overlap of differentially expressed genes in EpCAM+ IECs isolated from conventionally housed (CNV)-HDAC3ΔIEC mice versus Germ-free (GF)-HDAC3ΔIEC mice. Numbers of genes were determined by comparison of HDAC3ΔIEC mice to respective CNV- or GF-HDAC3FF controls. n=3 mice per group. (b) Number of significantly enriched pathways in HDAC3ΔIEC mice using DAVID pathway analysis (p<0.05). (c) Albumin measured by ELISA from fecal samples. n=3 mice per group. (d) H&E and (e) lysozyme stained small intestine. Bars, 20µm. (f) H&E stained large intestine. Bars, 50µm. (g, h) H&E stained large intestine from (g) CNV- or (h) GF-HDAC3FF or HDAC3ΔIEC mice after 4 days of 2.5% DSS administration. Bars, 100µm. Data are representative of two independent experiments. Results are shown as mean ± SEM.
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