Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches

Treveil, Agatha; Sudhakar, Padhmanand; Matthews, Zoe J.; Wrzesiński, Tomasz; Jones, Emily; Brooks, Johanne; Ölbei, Márton; Hautefort, Isabelle; Hall, Lindsay J.; Carding, Simon R.; Mayer, Ulrike; Powell, Penny P.; Wileman, Tom; Palma, Federica Di; Haerty, Wilfried; Korcsmáros, Tamás

doi:10.1039/c9mo00130a

Cited by 31 publications

(20 citation statements)

References 121 publications

(136 reference statements)

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“…The microbiome directed immune response and the stable localization over time is unlikely to be explained by a mere T-cell overresponse and, therefore, unlikely to represent an autoimmune disease (107). Future studies on the regulatory network of Paneth cells, maybe like those reported recently, using transcriptomics approaches may delineate additional complexity in these already remarkably versatile cells (114). Finally, and this is what counts for the patients: if the chance to substitute for mucosal defensins by systemic or oral administration, as mentioned above, really works out, this originally unlikely hypothesis may lead to a promising new therapy both in Crohn's disease (115,116) as well as in intestinal graft vs. host disease (117)…”

Section: Resultsmentioning

confidence: 82%

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease

Wehkamp

Stange

2020

Front. Immunol.

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The Paneth cells reside in the small intestine at the bottom of the crypts of Lieberkühn, intermingled with stem cells, and provide a niche for their neighbors by secreting growth and Wnt-factors as well as different antimicrobial peptides including defensins, lysozyme and others. The most abundant are the human Paneth cell α-defensin 5 and 6 that keep the crypt sterile and control the local microbiome. In ileal Crohn's disease various mechanisms including established genetic risk factors contribute to defects in the production and ordered secretion of these peptides. In addition, lifestyle risk factors for Crohn's disease like tobacco smoking also impact on Paneth cell function. Taken together, current evidence suggest that defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal, Crohn's disease by allowing bacterial attachment and invasion.

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Section: Resultsmentioning

confidence: 82%

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease

Wehkamp

Stange

2020

Front. Immunol.

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“…To identify ace2-expressing cells at single-cell resolution, we explored marker genes mouse and other organisms express in intestinal stem cells (mki67, pcna, bmib, Aghaallaei et al, 2016;Yu et al, 2018) absorptive enterocytes (alpi, vil1, slc34a2a, Makky et al, 2007;Wallace et al, 2005;Yang et al, 2012), peptide hormone-secreting enteroendocrine cells (gip, ccka, cckb, ghrl, gcga, gcgb, pyyb, anxa4, Crosnier et al, 2005;Sommer and Mostoslavsky, 2014;Zhang et al, 2014), and mucus-secreting goblet cells (mucin genes, agr2, Komiya et al, 1999;Lai et al, 2016;Treveil et al, 2020). Within the intestine, the zebrafish ortholog of mouse stem cell markers (e.g.…”

Section: What Is the Ace2-expressing Cell Type?mentioning

confidence: 99%

The SARS-CoV-2 receptor and other key components of the Renin-Angiotensin-Aldosterone System related to COVID-19 are expressed in enterocytes in larval zebrafish

et al. 2021

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People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with coronavirus SARS-CoV-2, which causes COVID-19. Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, counteracting its chronic effects, and serves as the SARS-CoV-2 receptor. Ace, the coronavirus, and COVID-19 comorbidities all regulate Ace2, but we do not yet understand how. To exploit zebrafish (Danio rerio) to help understand the relationship of the RAAS to COVID-19, we must identify zebrafish orthologs and co-orthologs of human RAAS genes and understand their expression patterns. To achieve these goals, we conducted genomic and phylogenetic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have one or more zebrafish orthologs or co-orthologs. Results identified a specific type of enterocyte as the specific site of expression of zebrafish orthologs of key RAAS components, including Ace, Ace2, Slc6a19 (SARS-CoV-2 co-receptor), and the Angiotensin-related peptide cleaving enzymes Anpep (receptor for the common cold coronavirus HCoV-229E), and Dpp4 (receptor for the Middle East Respiratory Syndrome virus, MERS-CoV). Results identified specific vascular cell subtypes expressing Ang II receptors, apelin, and apelin receptor genes. These results identify genes and cell types to exploit zebrafish as a disease model for understanding mechanisms of COVID-19.

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“…Nevertheless, an essential component is the mechanistic description of the targets of a given regulator, allowing computation of its footprint. With available SARS-CoV-2 related omics and interaction datasets [281], it is possible to infer which TFs and signalling pathways are affected upon infection [282]. Combining the COVID-19 Disease map regulatory interactions with curated collections of TF-target interactions like DoRothEA [283] will provide a contextualised evaluation of the effect of SARS-CoV-2 infection at the TF level.…”

Section: Footprint Based Analysismentioning

confidence: 99%

COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms

Ostaszewski

Niarakis

Mazein

et al. 2020

Preprint

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We hereby describe a large-scale community effort to build an open-access, interoperable, and computable repository of COVID-19 molecular mechanisms - the COVID-19 Disease Map. We discuss the tools, platforms, and guidelines necessary for the distributed development of its contents by a multi-faceted community of biocurators, domain experts, bioinformaticians, and computational biologists. We highlight the role of relevant databases and text mining approaches in enrichment and validation of the curated mechanisms. We describe the contents of the map and their relevance to the molecular pathophysiology of COVID-19 and the analytical and computational modelling approaches that can be applied to the contents of the COVID-19 Disease Map for mechanistic data interpretation and predictions. We conclude by demonstrating concrete applications of our work through several use cases.

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Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches

Abstract: We demonstrate the application of network biology techniques to increase understanding of intestinal dysbiosis through studying transcriptomics data from Paneth and goblet cell enriched enteroids.

Cited by 31 publications

References 121 publications

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease

The SARS-CoV-2 receptor and other key components of the Renin-Angiotensin-Aldosterone System related to COVID-19 are expressed in enterocytes in larval zebrafish

COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms

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