Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma

Kuester, Doerthe; Guenther, Thomas; Biesold, Susanne; Hartmann, Arndt; Bataille, Frauke; Ruemmele, Petra; Peters, Brigitte; Meyer, Frank; Schubert, Daniel; Bohr, Ulrich R. M.; Malfertheiner, Peter; Lippert, H.; Silver, Andrew; Roessner, Albert; Schneider‐Stock, Regine

doi:10.1016/j.prp.2010.05.004

Cited by 37 publications

(28 citation statements)

References 43 publications

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“…Indeed, the DAPK1 requirement for NLRP3 activation was stimulus dependent; NLRP3 activity was ablated upon DAPK deficiency in response to TLR2 and TLR7, but not TLR4 signaling (Chuang et al., 2011). As a matter of fact, LPS-induced intestinal inflammation was increased in DAPK1 deficiency in mice (Nakav et al., 2012) and humans where enhanced severity of gut inflammation and ulcerative colitis was observed (Kuester et al., 2010). Promotion of NLRP3 activity was meant to contribute to DAPK1-induced cell death (Chuang et al., 2011), an activity that we have not seen in the lung.…”

Section: Discussionmentioning

confidence: 99%

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Oikonomou

Moretti

Renga

et al. 2016

Cell Host & Microbe

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SummaryDefects in a form of noncanonical autophagy, known as LC3-associated phagocytosis (LAP), lead to increased inflammatory pathology during fungal infection. Although LAP contributes to fungal degradation, the molecular mechanisms underlying LAP-mediated modulation of inflammation are unknown. We describe a mechanism by which inflammation is regulated during LAP through the death-associated protein kinase 1 (DAPK1). The ATF6/C/EBP-β/DAPK1 axis activated by IFN-γ not only mediates LAP to Aspergillus fumigatus but also concomitantly inhibits Nod-like receptor protein 3 (NLRP3) activation and restrains pathogenic inflammation. In mouse models and patient samples of chronic granulomatous disease, which exhibit defective autophagy and increased inflammasome activity, IFN-γ restores reduced DAPK1 activity and dampens fungal growth. Additionally, in a cohort of hematopoietic stem cell-transplanted patients, a genetic DAPK1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility. Thus, DAPK1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by IFN-γ.

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Section: Discussionmentioning

confidence: 99%

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Oikonomou

Moretti

Renga

et al. 2016

Cell Host & Microbe

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“…DAP encodes a death associated protein and is a negative regulator of apoptosis. While previously associated with CD, expression of DAP kinase is linked to autophagy and is elevated in UC (Kuester et al 2010). …”

Section: Genetic Predispositionmentioning

confidence: 97%

Parallels Between Mammals and Flies in Inflammatory Bowel Disease

Christofi

Apidianakis

2015

Life Extension

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The intestinal hologenome lies at the center of intestinal homeostasis and disease. It is the sum of the host genome and the intestinal microbiome. During the last decade we came to appreciate the pivotal role of the microbiome in intestinal inflammation and concomitant diseases. Moreover environmental factors, predominantly diet, affect the microbiome and the host immune responses. Thus manipulation of intestinal microbiota and environmental factors are rightfully the focus of current research. The study of the hologenome necessitates not only clinical assessments but also the use of model organisms, for example, mice and flies. Despite the limitations imposed by the evolutionary distance between flies and mammals, Drosophila research provided us during the last few years with a wealth of information regarding intestinal inflammation and the role of microbiota. Conserved aspects of intestinal homeostasis and disease between flies and mice, for example in signalling pathways, the intestinal defence responses and the role of microbiota, consolidate and may advance the principles that govern intestinal inflammation in humans.

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“…22,[81][82][83] Both diseases states have commonalities in regards to symptom manifestation and genetic loci that are most often associated with immune regulation 83,84 as well as a the dysbiosis of the gut microbiota. 85 Many of the genes found to be commonly dysregulated, with correlating aberrant methylation patterns, in the genetics screens of UC affected tissue are associated with regulating apoptosis (Cdkn2a, 86,87 Dapk, 88,89 and Cdh1 90 ) and, in general, UC tissue shows overall genomic hypermethylation. 91 Even though the number of genetic loci associated with IBD is now over 200, up from 163, these loci only seem to contribute to 13.1% of the variance seen in CD patients and 8.2% in UC patients.…”

Section: Dna Methylation Dynamics In Inflammatory Bowel Diseasementioning

confidence: 99%

Role of DNA Methylation in the Development and Differentiation of Intestinal Epithelial Cells and Smooth Muscle Cells

Jorgensen

2019

J Neurogastroenterol Motil

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The mammalian intestine contains many different cell types but is comprised of 2 main cell types: epithelial cells and smooth muscle cells. Recent in vivo and in vitro evidence has revealed that various alterations to the DNA methylation apparatus within both of these cell types can result in a variety of cellular phenotypes including modified differentiation status, apoptosis, and uncontrolled growth. Methyl groups added to cytosines in regulatory genomic regions typically act to repress associated gene transcription. Aberrant DNA methylation patterns are often found in cells with abnormal growth/differentiation patterns, including those cells involved in burdensome intestinal pathologies including inflammatory bowel diseases and intestinal pseudo-obstructions. The altered methylation patterns being observed in various cell cultures and DNA methyltransferase knockout models indicate an influential connection between DNA methylation and gastrointestinal cells' development and their response to environmental signaling. As these modified DNA methylation levels are found in a number of pathological gastrointestinal conditions, further investigations into uncovering the causative nature, and controlled regulation, of this epigenetic modification is of great interest.

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Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma

Cited by 37 publications

References 43 publications

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Parallels Between Mammals and Flies in Inflammatory Bowel Disease

Role of DNA Methylation in the Development and Differentiation of Intestinal Epithelial Cells and Smooth Muscle Cells

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