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| Status |
Public on Nov 26, 2020 |
| Title |
Bone marrow monocytes from once-malaria infected mice have no epigenetic memory of the infection. |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Disease tolerance is an alternative strategy for acquired immunity to malaria and can be rapidly induced after a single malaria episode - in the absence of improved parasite clearance. Memory of a first malaria episode dampens the inflammatory profile of spleen monocytes and induces mechanisms of stress tolerance to minimise tissue damage. This begs the question how monocytes are instructed to respond in a different way to second compared to first malaria infection. We asked if malaria alters the epigenetic landscape of inflammatory monocytes before their release from the bone marrow - thus testing the compelling innate memory hypothesis. We compared the genome-wide distribution of histone modifications on flow-sorted bone marrow monocytes from mice with memory of severe mosquito transmitted P. chabaudi AJ infection (30 days after drug cure) and drug treated uninfected age-matched controls using ChIPseq. Specifically, we tested whether once-infected mice have long-lived modifications in i) transcription start sites marked with H3K27ac to activate transcription ii) enhancers or superenhancers marked with H3K4me1 to promote gene expression and iii) in H3K9me3 to condense DNA into heterochromatin thereby silencing gene expression.
We found no meaningful differences in the histone modification profiles of 2848 genes that define monocyte function in first and second malaria infection using the motif discovery software HOMER. Furthermore, when calling differentially modified regions (DMR) between once-infected mice and uninfected mice to ask whether there were any measurable differences in the epigenetic landscapes of these genes, we found 95% had no detectable modifications. In those rare cases where a DMR was called, HOMER assigned a low peak score, indicating low confidence and minimal biological relevance. Epigenetic reprogramming does therefore not underpin the functional specialisation of inflammatory monocytes in tolerised hosts. Innate memory is thus not induced by malaria infection in vivo. Instead, altered monocyte function and fate are imprinted within the spleen (link to GEO microarray) to promote disease tolerance.
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| Overall design |
C57Bl6/J mice were infected with mosquito transmitted P. chabaudi AJ, leading to an acute severe malaria episode and persisting chronic infection, which was drug treated using chloroquine after 40 days. 30 days after the start of drug treatment we assessed the enrichment of three histone modifications (H3K27ac, H3K4me1 and H3K9me3) in flow-sorted bone marrow monocytes relative to non-immunoprecipitated input. Histone modification profiles of genes that could promote or silence malaria responsive gene expression, and thus impart innate memory in once-infected mice, were compared to age-matched uninfected mice receiving an identical chloroquine regimen.
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| Contributor(s) |
Nahrendorf W, Ivens A, Spence PJ |
| Citation(s) |
33752799 |
| |
| Submission date |
May 13, 2020 |
| Last update date |
Mar 29, 2021 |
| Contact name |
Alasdair Ivens |
| E-mail(s) |
al.ivens@ed.ac.uk
|
| Phone |
44 131 6513605
|
| Organization name |
Centre for Immunity, Infection and Evolution
|
| Street address |
Kings Buildings
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| City |
Edinburgh |
| ZIP/Postal code |
EH9 3FL |
| Country |
United Kingdom |
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| Platforms (2) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (26)
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| This SubSeries is part of SuperSeries: |
| GSE150479 |
Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria. |
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| Relations |
| BioProject |
PRJNA632546 |
| SRA |
SRP261426 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE150478_H3K27ac_MEMORY_ChIP_AJ.bedGraph.gz |
2.2 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K27ac_MEMORY_ChIP_AJ.tagdir.tar.gz |
747.5 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K27ac_MEMORY_ChIP_AJ.tdf |
1.3 Gb |
(ftp)(http) |
TDF |
| GSE150478_H3K27ac_MEMORY_ChIP_AMC.bedGraph.gz |
1.9 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K27ac_MEMORY_ChIP_AMC.tagdir.tar.gz |
678.8 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K27ac_MEMORY_ChIP_AMC.tdf |
1.1 Gb |
(ftp)(http) |
TDF |
| GSE150478_H3K27ac_MEMORY_INPUT_AJ.bedGraph.gz |
3.7 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K27ac_MEMORY_INPUT_AJ.tagdir.tar.gz |
1.2 Gb |
(ftp)(http) |
TAR |
| GSE150478_H3K27ac_MEMORY_INPUT_AJ.tdf |
2.1 Gb |
(ftp)(http) |
TDF |
| GSE150478_H3K27ac_MEMORY_INPUT_AMC.bedGraph.gz |
3.9 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K27ac_MEMORY_INPUT_AMC.tagdir.tar.gz |
1.3 Gb |
(ftp)(http) |
TAR |
| GSE150478_H3K27ac_MEMORY_INPUT_AMC.tdf |
2.2 Gb |
(ftp)(http) |
TDF |
| GSE150478_H3K4me1_MEMORY_ChIP_AJ.bedGraph.gz |
1.4 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K4me1_MEMORY_ChIP_AJ.tagdir.tar.gz |
446.1 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K4me1_MEMORY_ChIP_AJ.tdf |
748.8 Mb |
(ftp)(http) |
TDF |
| GSE150478_H3K4me1_MEMORY_ChIP_AMC.bedGraph.gz |
2.5 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K4me1_MEMORY_ChIP_AMC.tagdir.tar.gz |
856.1 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K4me1_MEMORY_ChIP_AMC.tdf |
1.4 Gb |
(ftp)(http) |
TDF |
| GSE150478_H3K4me1_MEMORY_INPUT_AJ.bedGraph.gz |
1.7 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K4me1_MEMORY_INPUT_AJ.tagdir.tar.gz |
546.7 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K4me1_MEMORY_INPUT_AJ.tdf |
1011.2 Mb |
(ftp)(http) |
TDF |
| GSE150478_H3K4me1_MEMORY_INPUT_AMC.bedGraph.gz |
1.8 Gb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K4me1_MEMORY_INPUT_AMC.tagdir.tar.gz |
604.2 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K4me1_MEMORY_INPUT_AMC.tdf |
1.1 Gb |
(ftp)(http) |
TDF |
| GSE150478_H3K9me3_MEMORY_ChIP_AJ.bedGraph.gz |
960.3 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K9me3_MEMORY_ChIP_AJ.tagdir.tar.gz |
345.1 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K9me3_MEMORY_ChIP_AJ.tdf |
496.2 Mb |
(ftp)(http) |
TDF |
| GSE150478_H3K9me3_MEMORY_ChIP_AMC.bedGraph.gz |
950.6 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K9me3_MEMORY_ChIP_AMC.tagdir.tar.gz |
338.0 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K9me3_MEMORY_ChIP_AMC.tdf |
478.2 Mb |
(ftp)(http) |
TDF |
| GSE150478_H3K9me3_MEMORY_INPUT_AJ.bedGraph.gz |
700.6 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K9me3_MEMORY_INPUT_AJ.tagdir.tar.gz |
266.5 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K9me3_MEMORY_INPUT_AJ.tdf |
306.3 Mb |
(ftp)(http) |
TDF |
| GSE150478_H3K9me3_MEMORY_INPUT_AMC.bedGraph.gz |
526.9 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE150478_H3K9me3_MEMORY_INPUT_AMC.tagdir.tar.gz |
220.7 Mb |
(ftp)(http) |
TAR |
| GSE150478_H3K9me3_MEMORY_INPUT_AMC.tdf |
246.0 Mb |
(ftp)(http) |
TDF |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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