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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Organisations
People |
ORCID iD |
Patrick Varga-Weisz (Principal Investigator) |
Publications
Fachi JL
(2019)
Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism.
in Cell reports
Fellows R
(2020)
Chromatin dynamics and histone modifications in intestinal microbiota-host crosstalk
in Molecular Metabolism
Fellows R
(2018)
In vitro Enzymatic Assays of Histone Decrotonylation on Recombinant Histones.
in Bio-protocol
Corrêa R
(2023)
Inulin diet uncovers complex diet-microbiota-immune cell interactions remodeling the gut epithelium
in Microbiome
Fellows R
(2018)
Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases.
in Nature communications
Kazakevych J
(2020)
Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium.
in Genome biology
Kazakevych J
(2019)
Transcriptome analysis identifies a robust gene expression program in the mouse intestinal epithelium on aging.
in Scientific reports
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 |