Role of epigenetic changes induced by short chain fatty acids in the intestinal epithelium

Lead Research Organisation: Babraham Institute
Department Name: Nuclear Dynamics

Abstract

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Description This award was instrumental to forge a collaboration between the groups of Varga-Weisz (UK) and Marco Vinolo (Brazil) with complementary interests and skills. It let us ex[plore new mechanisms by which gut bacteria influence genome function in the cells of the gut lining. The gut is home to innumerable bacteria that are 'good bacteria' in that they help in digesting food, especially plant fibres. They also generate vitamines, help to fend off pathogenic bacteria and train and instruct the immune system. How these 'good bacteria' interact with the host is an important question for our understanding of health and disease. We provided new insights into this field through the discovery of a new mechanism by which the bacteria affect gene expression in the gut. The gut bacteria generate metabolites through their digestion of plant fibres. These metabolites, so called short chain fatty acids (SCFAs), are taking up by the gut cells. We showed new ways by which metabolites affect the packing of the host cells' genome which, in turn, affects gene regulation. We showed that SCFAs promote a new modification of the genome packaging, histone crotonylation. Furthermore, we demonstrated that the SCFAs achieve this by inhibiting a class of enzymes in the gut cells, including one called HDAC2. This is interesting, as these enzymes, including HDAC2, have been implicated in cancer and a drug targets to fight cancer.
Exploitation Route Our work will provide new insights and tools to explore meachanisms by which the microbiota and also diet affect gene expression in the intestinal epithelium. We also demonstrated a new enzymatic activity for key genome regulators, class I histone deacetylases (HDACs). These enzymes are exciting drug targets, e.g. in the fight against cancer. The new enzymatic assays that we published may help in the development of new drungs targeting HDACs.
Sectors Agriculture, Food and Drink,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
URL https://www.nature.com/articles/s41467-017-02651-5
 
Description Our research and its ensuing publication in Nature Communications was discussed in 24 News Outlets and a radio show, many with the emphasis on healthy nutrition, eating lots of vegetables and fruits etc. Thus, our work helped to raise the attention on healthy nutrition. It also raised awareness about the 'good gut bacteria'. Based on this work, I have obtained a Sao Paulo Chair of Excellence, funded by the Sao Paulo Research Foundation (FAPESP, why is this major funded NOT listed in your drop down menu of funders????). Funding is from 2020-2025 and we have used this to set up a single cell transcriptomics facility at the University of Campinas, UNICAMP.
First Year Of Impact 2020
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal
 
Description Acquisition of the Drosophila model system to understand mechanisms of innate immunity regulation by chromatin dynamics
Amount £64,940 (GBP)
Funding ID NC/W001047/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Public
Country United Kingdom
Start 06/2021 
End 06/2023
 
Title Analysis of histone decrotonylation 
Description We describe a method to measure histone decrotonylation in vitro. 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact We discovered that histone deacetylases (HDACs, more specifically class I HDACs) are also histone decrotonylases. This is important, as HDACs are important new drug targets in the fight against cancer. Our discovery may lead to more refined drug development. 
URL https://www.nature.com/articles/s41467-017-02651-5
 
Description Collaboration with Caroline Marcantonio Ferreira 
Organisation Federal University of São Paulo
Country Brazil 
Sector Academic/University 
PI Contribution We provided the overarching research question and expertise in chromatin analysis and gene expression.
Collaborator Contribution The group of Caroline Marcantonio Ferreira provided expertise in the measurement of short chain fatty acids.
Impact Paper: Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Fellows et al., Nat Commun. 2018 Jan 9;9(1):105. doi: 10.1038/s41467-017-02651-5.
Start Year 2017
 
Description Collaboration with Dr Jonathan Clark, Biological Chemistry, Babraham Institute 
Organisation Babraham Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided the overarching research question and expertise in chromatin biology, including histone modifications.
Collaborator Contribution Dr Jonathan Clark provided his expertise in chemistry to evaluate and develop histone decrotonylation assays,
Impact Paper: Nat Commun. 2018 Jan 9;9(1):105. doi: 10.1038/s41467-017-02651-5.
Start Year 2015
 
Description Collaboration with Marc Veldhoen 
Organisation Babraham Institute
Department Lymphocyte Signalling
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution My team provided expertise in chromatin analysis, including genome-wide profiling of histone modifications. We also contributed expertise in transcriptome analysis.
Collaborator Contribution Marc Veldhoen established gut organoid culture for our lab and provided reagents for this.
Impact Our collaboration resulted in a joint authorship: Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Fellows R, et al., Nat Commun. 2018 Jan 9;9(1):105. doi: 10.1038/s41467-017-02651-5.
Start Year 2013
 
Description Collaboration with Marc Veldhoen 
Organisation Babraham Institute
Department Lymphocyte Signalling
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution My team provided expertise in chromatin analysis, including genome-wide profiling of histone modifications. We also contributed expertise in transcriptome analysis.
Collaborator Contribution Marc Veldhoen established gut organoid culture for our lab and provided reagents for this.
Impact Our collaboration resulted in a joint authorship: Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Fellows R, et al., Nat Commun. 2018 Jan 9;9(1):105. doi: 10.1038/s41467-017-02651-5.
Start Year 2013
 
Description Collaboration with Professor Marco Aurelia Ramirez Vinolo and his lab, University of Campinas, Brazil 
Organisation State University of Campinas
Department Institute of Biology
Country Brazil 
Sector Academic/University 
PI Contribution As a result of meeting through the BBSRC-Brazil Partnering Award, my lab and the lab of Marco Vinolo set up a collaboration, in part funded through a BBSRC-FAPESP Pump priming Award. In this collaboration, my lab defined the overall research agenda, which was the elucidation of the link between the microbiota in the gut and gene regulation through histone modifications. My team and I provided the expertise in chromatin biology, histone modifications and the initial observation that have been generated, in aprt, in collaboration with Dr Tiziana Bonald, Italy. We also provided expertise in genome-wide chromatin and gene expression analysis. I also largely wrote the manuscript that was generated through this collaboration:Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases R Fellows etal., Nature communications 9 (1), 105; 10.1038/s41467-017-02651-5.
Collaborator Contribution The lab of Prof. Marco Vinolo provided expertise regarding then role and analysis of short chain fatty acids and manipulation of microbiota in mice. This expertise was pivotal for our work examining the role of microbiota in shaping chromatin and gene expression in the colon epithelium. Therefore, the BBSRC-Brazil partnering award was instrumental and succeeded in its aim to foster a productive collaboration between UK and Brazilian scientists.
Impact This collaboration resulted in a publication in Nature Communications that elicited much attention, as indicated by its current Altmetric score of 273: Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun. 2018 Jan 9;9(1):105. doi: 10.1038/s41467-017-02651-5.
Start Year 2015
 
Description Collaboration with TB 
Organisation European Institute of Oncology (IEO)
Country Italy 
Sector Academic/University 
PI Contribution provided research question and materials
Collaborator Contribution provided expert mass spec analysis
Impact Funded MRC project grant
Start Year 2013
 
Description Radio Interview at BBC 3 Cambridgeshire 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Radio Interviews of PhD student Rachel Fellows from the Varga-Weisz lab concerning her research on gut microbiota and gene regulation, in the wake of the publication of her paper.
Year(s) Of Engagement Activity 2018