Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide maps of H3K4me1 in Mycobacterium tuberculosis H37Rv-infected macrophages


ABSTRACT: Host macrophage transcriptional responses to intracellular pathogens remain poorly characterized. We screened transcriptional enhancers engaged in response to M. tuberculosis (Mtb) infection by ChIPseq analysis of histone H3 lysine 4 monomethylation (H3K4me1). De novo monomethylation during infection was associated with genes implicated in host defense and apoptosis. These regions were enriched for binding sites for ETS transcription factor family members and response elements for nuclear receptors, including liver X receptors (LXRs) and peroxisomal proliferator activated receptors (PPARs), many of which were encompassed by transposable elements. LXRa expression was strongly induced by infection, whereas that of PPARs was unaffected. LXR DNA binding and NCoR corepressor recruitment increased proportionately in infected cells but coactivator association was unchanged, consistent with a lack of induction of endogenous agonists. However, treatment of infected cells with LXR agonist T0901317 strongly increased coactivator recruitment and induced a gene expression program characterized by enhanced innate immune signaling and lipid metabolism. Remarkably, T0901317 treatment selectively induced apoptosis in infected macrophages, and was accompanied by Mtb death, reducing mycobacterial burden 18-fold relative to vehicle 5d after infection. These studies define macrophage transcriptional responses to Mtb infection, and suggest that tissue-specific LXRa agonists may be efficacious in clinical management of tuberculosis.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: David Laperriere 

PROVIDER: E-MTAB-3192 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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