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, In-Chan; Grunberg, Stephanie; Sinha, Rohini; Wynosky-Dolfi, Meghan A.; Snyder, Annelise G.; Giacomin, Paul; Joyce, Karen L.; Hoang, Tram B.; Bewtra, Meenakshi; Brodsky, Igor E.; Sonnenberg, Gregory F.; Bushman, Frederic D.; Won, Kyoung Jae; Lazar, Mitchell A.; Artis, David

doi:10.1038/nature12687

Cited by 212 publications

(209 citation statements)

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“…Commensal bacteriaderived signals also influence host epigenetic pathways, particularly through DNA and histone methylation [32][33][34][35][36] and histone acetylation and deacetylation [37][38][39][40][41] . The commensal microbiota produces multiple low-molecular-weight byproducts that modify the host cell epigenome and may alter the functional behavior of host cells.…”

Section: Special Issue (Mini Review) Gut Microbiota and Epigeneticsmentioning

confidence: 99%

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Takahashi

Hase

2015

Inflammation and Regeneration

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Commensal microbiota colonizing the digestive tract is a symbiotic partner of its host, as it plays a critical role in nutrient metabolism as well as the development and maturation of the host immune system. Although it is clear that regulation of the host-commensal relationship is crucial to mammalian health, the underlying mechanisms regulating gut homeostasis are yet to be elucidated. Epigenetic modifications, including DNA methylation and histone methylation/acetylation, alter the structure of chromatin to regulate the transcriptional program of eukaryotic cells. At the whole genome level, these modifications possibly play a key role in regulating the mutually beneficial relationship between the host and the gut microbiota. In this review, we describe how the commensal microbiota and its metabolic by-products modify the epigenome of host cells, and in turn, change their development and functional behavior.Rec.2/24/2015, Acc.3/1/2015, pp129-136

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Section: Special Issue (Mini Review) Gut Microbiota and Epigeneticsmentioning

confidence: 99%

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Takahashi

Hase

2015

Inflammation and Regeneration

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“…Antibiotic administration can impact transcript levels and histone modifications in IECs (Thaiss et al 2016); however, it's unclear if these changes are indirect effects caused by alterations to microbiota composition, direct effects of the antibiotic on host cells, or the effects of remaining antibiotic-resistant microbiota (Morgun et al 2015). Previous studies have shown that histone deacetylase 3 is required in IECs to maintain intestinal homeostasis in the presence of microbiota (Alenghat et al 2013) and that overall histone acetylation and methylation in the intestine is altered by microbiota colonization (Krautkramer et al 2016). However, the direct and specific effects of the microbiota on host CRRs and subsequent transcriptional responses in IECs remain unknown.…”

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confidence: 99%

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

et al. 2017

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Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.

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“…Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3,4,9,11,12), but direct links to the IBD intestinal pathology have not been established. However, recent work has shown that IEC-specific deletion of the histone deacetylase HDAC3 results in increased susceptibility to intestinal damage and inflammation, although specific molecular targets remain to be identified (13).…”

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confidence: 99%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

170

168

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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.inflammation | Uhrf1 | DNA methylation | tumor necrosis factor | zebrafish I ntestinal epithelial cells (IECs) function as a barrier to prevent luminal contents from accessing underlying tissues, and loss of barrier function is a crucial factor leading to the development of inflammatory bowel diseases (IBD) (1). IBD, including Crohn's disease and ulcerative colitis, are intestinal disorders of poorly understood origin thought to arise from genetic susceptibility, luminal microbiota, immune responses, and environmental factors (2-4). A key element in IBD onset is the up-regulation of the proinflammatory cytokine tumor necrosis factor (TNF) by various cell types including immune cells and IECs. TNF overexpression has been detected in the Paneth cells within the epithelium of human IBD patients (5), and anti-TNF treatments are used successfully to treat patients with Crohn's disease (6). Previous research in mice has demonstrated that intestinal TNF exposure leads to loss of barrier function (7), and overexpression of TNF in mouse IECs is sufficient to elicit an IBD phenotype (8). Despite its pathogenic relevance, the genetic mechanisms regulating TNF expression and IBD onset remain largely unknown.Genome-wide association studies have identified numerous susceptibility loci associated with IBD including ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) and the DNA methyltransferases DNMT1 and DNMT3a (9, 10), which are genes involved in DNA methylation controlling epigenetic transcriptional repression. Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3, 4, 9, 11, 12), but direct links to the I...

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Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

Cited by 212 publications

References 39 publications

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

Epigenetic control of intestinal barrier function and inflammation in zebrafish

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