Role of chromatin dynamics in regulation of intestinal innate immunity gene expression
Lead Research Organisation:
Babraham Institute
Department Name: Nuclear Dynamics
Abstract
In the intestine, a single layer of cells mediates the uptake of nutrients and creates a niche for beneficial microbes while at the same time it provides a barrier against invasion by pathogenic organisms. Important aspects of this defensive function are processes of innate immunity, which summarize various cell intrinsic mechanisms by which cells fend off pathogens. Examples for such processes are the secretion of anti-bacterial peptides and hydrolytic enzymes, detoxification processes and autophagy. If the barrier function of the intestine is impaired, this can lead to deadly infections but also devastating chronic, inflammatory diseases, such as Crohn's disease and ulcerative colitis. How the expression of factors involved in innate immunity processes is regulated and orchestrated is an important question with huge relevance to our understanding of health and disease.
In this application we will contribute towards this by building on exciting findings from our labs that link the packaging of the genome to the regulation of innate immunity genes in the intestine. We found that deletion in intestinal epithelial cells of an enzyme that regulates the packaging of the genome (a chromatin remodeling factor) renders mice more resistant to experimentally induced colitis. This unprecedented finding appears to be linked to the fact that the mice without this factor over-express many genes involved in innate immunity even without any challenge. Thus, this factor appears to orchestrate the regulation of many genes involved in innate immunity. Furthermore, in the absence of this factor we find changes in the packaging of many gene regulatory elements closely linked to genes, including many genes involved in innate immunity. We hypothesize that these changes facilitate the expression of these genes and may represent a general mechanism by which cells adapt to stress.
We wish to test these ideas and examine if the changes we observe are linked to the colitis response. This work will reveal potential new diagnostic markers and therapeutic targets for intestinal inflammatory conditions, while providing insights into very fundamental gene regulatory processes.
In this application we will contribute towards this by building on exciting findings from our labs that link the packaging of the genome to the regulation of innate immunity genes in the intestine. We found that deletion in intestinal epithelial cells of an enzyme that regulates the packaging of the genome (a chromatin remodeling factor) renders mice more resistant to experimentally induced colitis. This unprecedented finding appears to be linked to the fact that the mice without this factor over-express many genes involved in innate immunity even without any challenge. Thus, this factor appears to orchestrate the regulation of many genes involved in innate immunity. Furthermore, in the absence of this factor we find changes in the packaging of many gene regulatory elements closely linked to genes, including many genes involved in innate immunity. We hypothesize that these changes facilitate the expression of these genes and may represent a general mechanism by which cells adapt to stress.
We wish to test these ideas and examine if the changes we observe are linked to the colitis response. This work will reveal potential new diagnostic markers and therapeutic targets for intestinal inflammatory conditions, while providing insights into very fundamental gene regulatory processes.
Technical Summary
How chromatin dynamics in the intestinal epithelium orchestrates innate immunity is an important question but little is known about it. Our hypothesis is that chromatin dynamics, especially changes of histone variant H2AZ occupancy over CpG islands, regulate innate immunity gene expression in intestinal epithelium cells. We propose that histone H2AZ occupancy relates to cellular stress and the innate immunity response, e.g., during exposure to microbes, may reflect such a stress.
To test this, we will exploit a very well established colitis model in the mouse, Dextran Sodium Sulfate (DSS) mediated colitis, and focus on the role of two chromatin remodeling factors that promote (EP400) and counteract (Smarcad1) histone H2AZ occupancy. We will examine an exciting new histone modification, crotonylation, which we find is affected by chromatin remodeling and may be linked to H2AZ occupancy and possible the microbiota.
We will use chromatin immunoprecipitation coupled to high-throughput sequencing (ChIPseq) approaches to map histone H2AZ, histone crotonylation and chromatin remodeling factor occupancy during normal and colitis conditions and link these occupancies to a detailed analysis of the transcriptome, including the noncoding transcriptome. We will systematically examine CpG island chromatin using mass spectrometry approaches under all these conditions.
Our work will test if chromatin remodeling factors are involved in coordinating an innate immunity response. Together, data generated in this proposal will paint a detailed picture how the transcriptome in colon epithelial cells is affected during colitis and how chromatin dynamics prime these cells to respond to an insult.
To test this, we will exploit a very well established colitis model in the mouse, Dextran Sodium Sulfate (DSS) mediated colitis, and focus on the role of two chromatin remodeling factors that promote (EP400) and counteract (Smarcad1) histone H2AZ occupancy. We will examine an exciting new histone modification, crotonylation, which we find is affected by chromatin remodeling and may be linked to H2AZ occupancy and possible the microbiota.
We will use chromatin immunoprecipitation coupled to high-throughput sequencing (ChIPseq) approaches to map histone H2AZ, histone crotonylation and chromatin remodeling factor occupancy during normal and colitis conditions and link these occupancies to a detailed analysis of the transcriptome, including the noncoding transcriptome. We will systematically examine CpG island chromatin using mass spectrometry approaches under all these conditions.
Our work will test if chromatin remodeling factors are involved in coordinating an innate immunity response. Together, data generated in this proposal will paint a detailed picture how the transcriptome in colon epithelial cells is affected during colitis and how chromatin dynamics prime these cells to respond to an insult.
Planned Impact
More than 200 000 patients are though to suffer of Crohn's disease or ulcerative colitis in the UK currently (www.crohnsandcolitis.org.uk), but the numbers of patients is rising worldwide, potentially linked to changes in life style and nutrition. Inflammatory bowel diseases are often devastating and can currently only be treated, but not cured. Novel approaches and ways of thinking with regards to these diseases have the potential to bring new advances in diagnosis and treatment. Little is known how genome-regulatory processes such as chromatin dynamics impact these conditions, despite the emerging view that epigenetic processes may have an important influence in disease occurrence. It is remarkable that several chromatin remodeling factors, including those that are the subject of this proposal, are linked to Crohn's disease by genome-wide association studies (see: www.gwascentral.org/). Our work aims to benefit patients of intestinal inflammatory diseases. Our research may provide novel diagnostic markers and therapeutic targets. We find that deletion of chromatin remodeling factor Smarcad1 renders mice relatively resistant to colitis. In the future, small molecule inhibitors of this or other factors that regulate for example H2AZ function may help improve the conditions for patients of inflammatory bowel diseases. The recent discovery of 'histone mimics' such as the BET inhibitors (I-BET) as promising new drugs to combat cancer and inflammation show that such ideas are not far-fetched. Our observation that up-regulation of osteocalcins is linked to this resistance is very exciting and may link to novel therapeutic avenues. We will test if an up-regulation of features we connect to colitis in this proposal such as histone variants H2AZ, histone crotonylation and others can be identified in tissue slices using immuno-histochemistry and thus may have potential diagnostic value.
Our research will highlight the molecular requirements for a healthy intestine during steady state conditions, identify novel genes involved in tissue homeostasis, preventing intestinal disease and could elucidate the genetic predisposition to intestinal challenges, e.g., through pathogenic bacteria. All of which has important health benefits for the general public, who will benefit from a better understanding of the mechanisms of intestinal immunity and homeostasis. We hope to engage the general public, and specifically students and teachers, with our scientific research about the link between genome regulation and intestinal health. The potential health implications for patients and the elderly suffering conditions affecting the gut, such as inflammatory bowel disease or autoimmune diseases, including coeliac disease, are innumerable. Furthermore, understanding the molecular basis for disorders of the gut will allow health care providers and policy makers to make more informed decisions, both when treating patients and setting clinical policy.
The outcome of the research will be of interest to the R&D sector, both within the UK and internationally. Identifying the genetic disposition to intestinal diseases and new mouse models could lead to the development of new drugs or novel diagnostic approaches. As well as the obvious patient benefits, this will enhance the commercial impact and competitiveness of the investigators and their industrial partners. The proposed research will provide large data sets representing gene expression (transcriptomes, RNA-seq) and chromatin states (ChIP-seq) in various cell types, including intestinal stem cells, which will be made freely available following publication. This data will benefit researchers in academic and business sectors. For more information on specific collaborations please refer to the Academic Beneficiaries section.
The grant will employ a junior postdoctoral researcher and support advanced training in a diverse range of areas. We will also train internship students and other sceintists.
Our research will highlight the molecular requirements for a healthy intestine during steady state conditions, identify novel genes involved in tissue homeostasis, preventing intestinal disease and could elucidate the genetic predisposition to intestinal challenges, e.g., through pathogenic bacteria. All of which has important health benefits for the general public, who will benefit from a better understanding of the mechanisms of intestinal immunity and homeostasis. We hope to engage the general public, and specifically students and teachers, with our scientific research about the link between genome regulation and intestinal health. The potential health implications for patients and the elderly suffering conditions affecting the gut, such as inflammatory bowel disease or autoimmune diseases, including coeliac disease, are innumerable. Furthermore, understanding the molecular basis for disorders of the gut will allow health care providers and policy makers to make more informed decisions, both when treating patients and setting clinical policy.
The outcome of the research will be of interest to the R&D sector, both within the UK and internationally. Identifying the genetic disposition to intestinal diseases and new mouse models could lead to the development of new drugs or novel diagnostic approaches. As well as the obvious patient benefits, this will enhance the commercial impact and competitiveness of the investigators and their industrial partners. The proposed research will provide large data sets representing gene expression (transcriptomes, RNA-seq) and chromatin states (ChIP-seq) in various cell types, including intestinal stem cells, which will be made freely available following publication. This data will benefit researchers in academic and business sectors. For more information on specific collaborations please refer to the Academic Beneficiaries section.
The grant will employ a junior postdoctoral researcher and support advanced training in a diverse range of areas. We will also train internship students and other sceintists.
Organisations
- Babraham Institute (Lead Research Organisation)
- University of Strasbourg (Collaboration)
- Quadram Institute Bioscience (Collaboration)
- University of Lisbon (Collaboration)
- Babraham Institute (Collaboration)
- Federal University of São Paulo (Collaboration)
- European Institute of Oncology (IEO) (Collaboration)
- State University of Campinas (Collaboration)
Publications
Fellows R
(2018)
In vitro Enzymatic Assays of Histone Decrotonylation on Recombinant Histones.
in Bio-protocol
Fachi JL
(2019)
Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism.
in Cell reports
Kazakevych J
(2020)
Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium.
in Genome biology
Corrêa R
(2023)
Inulin diet uncovers complex diet-microbiota-immune cell interactions remodeling the gut epithelium
in Microbiome
Fellows R
(2020)
Chromatin dynamics and histone modifications in intestinal microbiota-host crosstalk.
in Molecular metabolism
Fellows R
(2018)
Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases.
in Nature communications
Mukherjee D
(2022)
Host lung microbiota promotes malaria-associated acute respiratory distress syndrome.
in Nature communications
Kazakevych J
(2019)
Transcriptome analysis identifies a robust gene expression program in the mouse intestinal epithelium on aging.
in Scientific reports
Nirello VD
(2022)
Does chromatin function as a metabolite reservoir?
in Trends in biochemical sciences
El-Sahhar S
(2022)
Functional Microbiomes
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 |
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 |
Title | Additional file 10 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 10: Table S9. Supplementary phenotype data for the DSS-induced colitis experiments (Fig. 6a, b and Additional file 1: Fig. S6a, b). DAI (disease activity index) scores were determined for each experiment separately, based on weight loss and a selection of fecal blood, stool consistency and overall animal appearance scores. Detailed scoring tables described in the according tab. Colon length after DSS-induction was determined in experiment 2 (Fig. 6b and Additional file 1: Fig. S6b). |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_10_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 10 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 10: Table S9. Supplementary phenotype data for the DSS-induced colitis experiments (Fig. 6a, b and Additional file 1: Fig. S6a, b). DAI (disease activity index) scores were determined for each experiment separately, based on weight loss and a selection of fecal blood, stool consistency and overall animal appearance scores. Detailed scoring tables described in the according tab. Colon length after DSS-induction was determined in experiment 2 (Fig. 6b and Additional file 1: Fig. S6b). |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_10_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 11 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 11: Table S10. Differentially expressed genes on Smarcad1-KO in control, microbiome enriched whole colon tissue samples. Gene lists as shown in Additional file 1: Fig. S9a. Table contents: Gene name, chromosomal position, DESeq2 FDR (cut-off 0.05), gene ID, gene description, average expression levels (log2 normalized to total reads) in WT/KO control (n = 3) and colitis (n = 5) data sets. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_11_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 11 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 11: Table S10. Differentially expressed genes on Smarcad1-KO in control, microbiome enriched whole colon tissue samples. Gene lists as shown in Additional file 1: Fig. S9a. Table contents: Gene name, chromosomal position, DESeq2 FDR (cut-off 0.05), gene ID, gene description, average expression levels (log2 normalized to total reads) in WT/KO control (n = 3) and colitis (n = 5) data sets. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_11_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 12 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 12: Table S11. Differentially expressed genes on Smarcad1-KO in microbiome enriched, DSS-induced colitis, whole colon tissue samples. Gene lists as shown in Additional file 1: Fig. S9b. Table contents: Gene name, chromosomal position, DESeq2 FDR (cut-off 0.05), gene ID, gene description, average expression levels (log2 normalized to total reads) in WT/KO control (n = 3) and colitis (n = 5) data sets. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_12_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 12 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 12: Table S11. Differentially expressed genes on Smarcad1-KO in microbiome enriched, DSS-induced colitis, whole colon tissue samples. Gene lists as shown in Additional file 1: Fig. S9b. Table contents: Gene name, chromosomal position, DESeq2 FDR (cut-off 0.05), gene ID, gene description, average expression levels (log2 normalized to total reads) in WT/KO control (n = 3) and colitis (n = 5) data sets. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_12_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 13 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 13: Table S12. Genes identified with the DESeq2 test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_13_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 13 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 13: Table S12. Genes identified with the DESeq2 test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_13_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 14 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 14: Table S13. Subset of gene list in Additional file 13: Table S12, indicated as cluster A in Fig. 8a. Genes were identified by hierarchical clustering in SeqMonk. Table contents: Gene name, chromosomal position. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_14_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 14 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 14: Table S13. Subset of gene list in Additional file 13: Table S12, indicated as cluster A in Fig. 8a. Genes were identified by hierarchical clustering in SeqMonk. Table contents: Gene name, chromosomal position. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_14_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 15 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 15: Table S14. Subset of gene list in Additional file 13: Table S12, indicated as clusters 1-4 in Fig. 8b. Genes were identified by hierarchical clustering in Seqmonk. Table contents: Gene name, selected annotations, cluster membership. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_15_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 15 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 15: Table S14. Subset of gene list in Additional file 13: Table S12, indicated as clusters 1-4 in Fig. 8b. Genes were identified by hierarchical clustering in Seqmonk. Table contents: Gene name, selected annotations, cluster membership. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_15_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 16 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 16: Table S15. List of genes with colonic expression (whole tissue, see Fig. 8), defined as detectable expression in either all WT/KO ctrl or all WT/KO colitis samples. Table contents: Gene name, chromosomal position, normalized linear read counts by sample. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_16_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 16 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 16: Table S15. List of genes with colonic expression (whole tissue, see Fig. 8), defined as detectable expression in either all WT/KO ctrl or all WT/KO colitis samples. Table contents: Gene name, chromosomal position, normalized linear read counts by sample. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_16_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 17 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 17: Table S16. List of enriched gene ontology terms of clusters 2 (Additional file 15: Table S14) versus all genes expressed in the colon (Additional file 16: Table S15) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_17_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 17 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 17: Table S16. List of enriched gene ontology terms of clusters 2 (Additional file 15: Table S14) versus all genes expressed in the colon (Additional file 16: Table S15) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_17_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 18 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 18: Table S17. List of enriched gene ontology terms of clusters 2 (Additional file 15: Table S14) versus all genes significantly upregulated in WT upon colitis (marked as UP in Additional file 13: Table S12) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_18_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 18 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 18: Table S17. List of enriched gene ontology terms of clusters 2 (Additional file 15: Table S14) versus all genes significantly upregulated in WT upon colitis (marked as UP in Additional file 13: Table S12) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_18_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 19 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 19: Table S18. List of enriched gene ontology terms of cluster A (Additional file 14: Table S13) versus all genes significantly upregulated in WT upon colitis (Additional file 13: marked as UP in Table S12) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_19_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 19 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 19: Table S18. List of enriched gene ontology terms of cluster A (Additional file 14: Table S13) versus all genes significantly upregulated in WT upon colitis (Additional file 13: marked as UP in Table S12) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_19_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 2 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 2: Table S1. Full statistical analysis data and annotation for the Fig. 3d, 4c, 5b, 6a,b,d, 7a and Additional file 1: Figures S1b-d, S3b,d-f, S4b,c, S6c-f. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_2_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 2 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 2: Table S1. Full statistical analysis data and annotation for the Fig. 3d, 4c, 5b, 6a,b,d, 7a and Additional file 1: Figures S1b-d, S3b,d-f, S4b,c, S6c-f. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_2_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 20 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 20: Table S19. List of enriched gene ontology terms of clusters 3/4 (Table S14) versus all genes expressed in the colon (Additional file 16: Table S15) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_20_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 20 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 20: Table S19. List of enriched gene ontology terms of clusters 3/4 (Table S14) versus all genes expressed in the colon (Additional file 16: Table S15) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_20_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 21 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 21: Table S20. List of enriched gene ontology terms of WT colon genes upregulated in colitis (Additional file 13: Table S12, marked UP) versus all genes expressed in the colon (Additional file 16: Table S15) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_21_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 21 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 21: Table S20. List of enriched gene ontology terms of WT colon genes upregulated in colitis (Additional file 13: Table S12, marked UP) versus all genes expressed in the colon (Additional file 16: Table S15) with a statistical cutoff p |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_21_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 22 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 22: Table S21. Principle Component Analysis based on OTU abundance in stool samples. Full list of 42 principal component values by sample. PC1 and PC2 shown in Additional file 1: Fig. S8a. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_22_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 22 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 22: Table S21. Principle Component Analysis based on OTU abundance in stool samples. Full list of 42 principal component values by sample. PC1 and PC2 shown in Additional file 1: Fig. S8a. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_22_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 23 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 23: Table S22. All detected OTUs annotated with counts per sample. Sublists marked in Additional file 1: Fig. S8b are marked as follows: red: OTUs not transferred from donor to recipients. Green: Candidate OTUs for enhanced colitis response and Smarcad1-mediated susceptibility. Table contents: OTU ID, detection counts per sample, digital indicators of presence in initial, donor and enriched microbiota, indicators of transferred (green) and un-transferred (red) OTUs, taxonomic information. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_23_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 23 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 23: Table S22. All detected OTUs annotated with counts per sample. Sublists marked in Additional file 1: Fig. S8b are marked as follows: red: OTUs not transferred from donor to recipients. Green: Candidate OTUs for enhanced colitis response and Smarcad1-mediated susceptibility. Table contents: OTU ID, detection counts per sample, digital indicators of presence in initial, donor and enriched microbiota, indicators of transferred (green) and un-transferred (red) OTUs, taxonomic information. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_23_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 24 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 24: Table S23. EdU assay example files and Excel-script for calculation of EdU-signal to crypt base distance. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_24_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 24 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 24: Table S23. EdU assay example files and Excel-script for calculation of EdU-signal to crypt base distance. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_24_of_Smarcad1_mediates_microbiota-indu... |
Title | Additional file 3 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 3: Table S2. Differentially expressed genes on Smarcad1-KO in ISC, TA, AE and small intestine derived organoids. Gene lists and their overlaps as shown in Additional file 1: Fig. S2a. Table contents: Gene name, chromosomal position, DESeq2 FDR, gene ID, gene description, average expression levels (n = 3, log2 normalized to total reads) in the corresponding RNA-seq dataset. Separate tab comparing the 4 lists (ISC, TA, AE, organoids). Separate tabs listing all genes expressed in small intestinal organoids and colon crypts (sorted cell and whole crypt datasets combined). |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_3_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 3 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 3: Table S2. Differentially expressed genes on Smarcad1-KO in ISC, TA, AE and small intestine derived organoids. Gene lists and their overlaps as shown in Additional file 1: Fig. S2a. Table contents: Gene name, chromosomal position, DESeq2 FDR, gene ID, gene description, average expression levels (n = 3, log2 normalized to total reads) in the corresponding RNA-seq dataset. Separate tab comparing the 4 lists (ISC, TA, AE, organoids). Separate tabs listing all genes expressed in small intestinal organoids and colon crypts (sorted cell and whole crypt datasets combined). |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_3_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 4 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 4: Table S3. Differentially expressed genes on Smarcad1-KO in whole colon crypts and flow cytometry-sorted colon epithelium. Gene lists and their overlaps as shown in Additional file 1: Fig. S2b. Table contents: Gene name, chromosomal position, DESeq2 FDR, gene ID, gene description, average/by sample expression levels (n = 3, log2 normalized to total reads) in the corresponding RNA-seq dataset. Separate Tab comparing the 2 lists (crypts, sorted epithelial cells). |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_4_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 4 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 4: Table S3. Differentially expressed genes on Smarcad1-KO in whole colon crypts and flow cytometry-sorted colon epithelium. Gene lists and their overlaps as shown in Additional file 1: Fig. S2b. Table contents: Gene name, chromosomal position, DESeq2 FDR, gene ID, gene description, average/by sample expression levels (n = 3, log2 normalized to total reads) in the corresponding RNA-seq dataset. Separate Tab comparing the 2 lists (crypts, sorted epithelial cells). |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_4_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 5 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 5: Table S4. Genes identified with the DESeq2 test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_5_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 5 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 5: Table S4. Genes identified with the DESeq2 test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_5_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 6 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 6: Table S5. Differential H3K9me3 MACS-peaks identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_6_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 6 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 6: Table S5. Differential H3K9me3 MACS-peaks identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_6_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 7 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 7: Table S6. Differential H3K9me2 MACS-peaks (300 bp fragment size) identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_7_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 7 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 7: Table S6. Differential H3K9me2 MACS-peaks (300 bp fragment size) identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_7_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 8 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 8: Table S7. Differential H3K9me3 MACS-peaks identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_8_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 8 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 8: Table S7. Differential H3K9me3 MACS-peaks identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_8_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 9 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 9: Table S8. Differential chromatin accessibility MACS-peaks (300 bp fragment size) identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_9_of_Smarcad1_mediates_microbiota-induc... |
Title | Additional file 9 of Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium |
Description | Additional file 9: Table S8. Differential chromatin accessibility MACS-peaks (300 bp fragment size) identified with the EdgeR test (cut-off FDR |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/Additional_file_9_of_Smarcad1_mediates_microbiota-induc... |
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 Falk Hildebrand, QUADRAM INSTITUE |
Organisation | Quadram Institute Bioscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have collaboraqted on a GCRF MRC grant application with Vietnamese partners. The application was not funded, but we will resubmit. |
Collaborator Contribution | Intellectual contribution, expertise. |
Impact | GCRF MRC grant application. |
Start Year | 2019 |
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 Dr Naiara Beraza, QUADRAM INSTITUE |
Organisation | Quadram Institute Bioscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We (Patrick Varga-Weisz) study novel histone modifications in germfree mice and controls. |
Collaborator Contribution | Dr Naiara Beraza provided tissue from germfree mice and controls. |
Impact | We are preparing a manuscript using data that have been obtained through the help of this collaboration. |
Start Year | 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 |
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 Prof Maria Mota |
Organisation | Institute of Molecular Medicine |
Country | Portugal |
Sector | Academic/University |
PI Contribution | We were involved in microbiome analysis of lung and gut tissue in mouse with respect to Malaria pathogenesis. This work is now published in Nature Communications. |
Collaborator Contribution | They provided the research question and model systems. |
Impact | Host lung microbiota promotes malaria-associated acute respiratory distress syndrome. Mukherjee D, Chora ÂF, Lone JC, Ramiro RS, Blankenhaus B, Serre K, Ramirez M, Gordo I, Veldhoen M, Varga-Weisz P, Mota MM. Nat Commun. 2022 Jun 29;13(1):3747. doi: 10.1038/s41467-022-31301-8. PMID: 35768411 |
Start Year | 2020 |
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 Professors Dominique Ferrandon and Samuel Liegeois, University of Strasbourg, France |
Organisation | University of Strasbourg |
Country | France |
Sector | Academic/University |
PI Contribution | We organised a workshop in using Drosophila in biomedical research at the University of Campinas, in substantial part funded by NC3Rs, and invited Drs Ferrandon and Liegeiois to Participate. |
Collaborator Contribution | The grant we have with NC3Rs is a Skills and Knowledge Transfer grant, and was designed to transfer expertise in using Drosophila for infection research from the labs of Prof Dominique Ferrandon and Samuel Liegeois, University of Strasbourg. They hosted us for 1 week for relevant training in their lab. in September 2021. |
Impact | We organised a workshop in using Drosophila in biomedical research at the University of Campinas, in substantial part funded by NC3Rs, and invited Drs Ferrandon and Liegeiois to Participate. |
Start Year | 2021 |
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 | Presentation to the House of Lords Science and Technology Committee on microbiome-host research in 2020 (https://www.caprisa.org/NewsAndEvents/Read/10494). |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | I spoke to the House of Lords Science and Technology Committee as expert on microbiome-host research in 2020 (https://www.caprisa.org/NewsAndEvents/Read/10494). |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.caprisa.org/NewsAndEvents/Read/10494 |