Role and mechanisms of gene silencing and heterochromatin in lymphocyte development

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

For normal cell function, it is equally important to switch on and switch off the correct genes in the correct cells. We have discovered an important factor, Smarcad1, that switches of large parts of the genome in cells where this is necessary. In this project we will remove this factor in B and T cells which are the major cells that fight infection in the body. We will determine what role this factor plays in helping these cells to perform their specialized functions, in particular which genes are switched off by Smarcad1.

Publications

10 25 50
 
Description The packaging of the genome, referred to as chromatin, is central to genome regulation. This occurs in part by packing the genome tightly (called heterochromatin) or unpacking the genome. Smarcad1 is a chromatin remodeling factor for which we have shown a role in heterochromatin maintenance through replication in cells in culture (Rowbotham et al., Mol Cell 2011). The task of this grant was to explore, if this factor has this role in immune cells, primarilly B and T cells (important immune cells of adaptive immunity), including during their development. We analyzed the role of Smarcad1 in B and T cell development in bone marrow and also B and T cell populations in the spleen using conditional knockout animals (where this factor is deleted in the T and B cells early on during their development). We also explored the role of this factor in generating mature immunoglobulins in a process called somatic hypermutation. We did not find a clear effect of Smarcad1 deletion in B and T cell development or somatic hypermutation. However, we found that this factor has a role in the maintenance of a specific set of T cells in the intestinal epithelium, intraepithelial lymphocytes. These cells are thought to have an important role in intestinal immunity by providing a first layer of defense. The exploration of the role of Smarcad1 in iIELs is ongoing. However, we widened the analysis and explore the role of Smarcad1 in intestinal immunity both in the iIELs and also the cells that make up the majority of the epithelium. Indeed, we find that in intestinal epithelium cells Smarcad1 is involved in the regulation of many factors acting in immunity, such as anti-bacterial peptides, This work led to a funded grant application from the MRC. In summary, our work shows (1) a role of Smarcad1 in intestinal immunity, and (2) demonstrates that this occurs, at least in part, through its role in gene regulation. Furthermore, this work ultimately led us to explore the role of microbioal products, so called short chain fatty acids (SCFAs), generated by their digestion of plant fibres, in the regulatin of chromatin and gene expression. This work showed that SCFAs affect genome function through their impact on a recently identified modification of chromatin called histone crotonylation. This work is now published (Fellows et al., Nat Comms. 2018).
Exploitation Route Our work will illuminate mechanisms of intestinal health and immunity. Our findings, in the long run, may help in science based decisions concerning healthy nutrition advice. Furtherrmore, by studying molecules involved in intestinal immunity and health, we may provide new rationals for drug targets and design.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description This work programm aimed at illuminating if chromatin remodeling factor Smarcad1 is involved in B- or T-cell development or maintenance. We found that deletion of Smarcad1 did not affect B- and T-cell numbers in bone marrow, speen and thymus. However, it did specifically affect intraepithelial lymphocytes of the intestine. Therefore, we explored the role of Smarcad1 in intestinal immunity further. The preliminary data that we obtained ultimately led to a successful project grant application to the MRC and two applications to the BBSRC (a third has been just submitted). Therefore, this grant was successful, as this was primarily a pump priming type of award.
First Year Of Impact 2012
Sector Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description BBSRC-Brazil Partnering Award
Amount £76,021 (GBP)
Funding ID BB/L026988/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2014 
End 10/2018
 
Description FAPESP Pump-Priming Awards
Amount £13,500 (GBP)
Funding ID BB/N013565/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2015 
End 05/2017
 
Description MRC project grant
Amount £406,182 (GBP)
Funding ID MR/N009398/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 02/2019
 
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, Babraham Institute 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution We investigate the role of chromatin remodeling by Smarcad1 in maintenance of intestinal immunity, especially of intraepithelial lymphocytes.
Collaborator Contribution Expertise in intestinal immunity.
Impact This work led to a grant application to the BBSRC (not successful) and a joint application to the EU under the HORIZON 2020 programme.
Start Year 2012
 
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 Charity/Non Profit 
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