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Diet-induced obesity dysregulates rapid epigenetic response to hypoxia in macrophages (ChIP-Seq)

ABSTRACT: Macrophages play important roles in tissue homeostasis and tissue healing process. The response to hypoxic environment is a trigger to induce key signaling pathways in macrophages. Functions of macrophages are dysregulated in metabolic diseases such as diabetes and obesity resulting in poor tissue healing. Epigenetic status including histone modification in macrophages is regulated by hypoxia. However, whether and how obesity influences histone modification under hypoxia is unknown. Using chromatin immunoprecipitation-sequencing (ChIP-seq), RNA-seq on mouse bone marrow-derived macrophages, we sought to determine whether hypoxia alters histone 3-lysine 4 trimethylation (H3K4me3) and gene expression profile in macrophages and how obesity influences H3K4me3 enrichment on the genome in hypoxia-dependent and -independent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE231991 | GEO | 2024/05/05

REPOSITORIES: GEO

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Project description:Inflammatory responses triggered by either microbial or endogenous stimuli rely on a complex transcriptional program that involves the differential expression of hundreds of genes. Jmjd3, a JmjC family histone demethylase (HDM), is quickly induced by the transcription factor NF-kB in response to inflammatory stimuli. Jmjd3 erases a histone mark associated with transcriptional repression and silencing, trimethylated lysine 27 in histone H3 (H3K27me3). Thus, Jmjd3-mediated demethylation of H3K27me3 links inflammation to the control of a histone modification involved in lineage determination, differentiation and tissue homeostasis. However, the specific contribution of Jmjd3 induction to innate immunity and inflammation remains unknown. Here we combined genome-wide mapping and gene knockout studies to investigate this issue. Chromatin immunoprecipitation (ChIP) coupled to ultra high-throughput sequencing (ChIP-Seq) in LPS-stimulated primary mouse macrophages demonstrated that Jmid3 is recruited to a large number of genomic targets with a strong preference for active transcription start sites (TSS). Virtually all Jmjd3-bound TSSs were characterized by high levels of H3K4me3, a marker of gene activity, and high levels of RNA polymerase II (Pol_II). Inducible genes showing a strong increase in H3K4me3 and Pol_II recruitment after endotoxin treatment (including those encoding several cytokines, chemokines and antiviral proteins) were in most cases Jmjd3-associated. In Jmjd3-knockout macrophages, initial RNA_Pol II recruitment and activation of Jmjd3 target genes was unaffected, but RNA_Pol II was prematurely released, thus resulting in non-sustained responses. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and transcriptional effects of Jmjd3 absence in the window of time analyzed here were uncoupled from measurable effects on this histone mark. Our data indicate that Jmjd3 is the effector of an NF-kB-controlled feed-forward transcriptional loop pervasively sustaining inflammatory transcriptional responses in a manner that is independent of H3K27me3 demethylation, and suggest the possible use of anti-Jmjd3 drugs to dampen pathologic inflammation. Keywords: Epigenetics Genome wide maps of histone demethylase jmjd3, the histone marks H3K4me3 and H3K27me3, and RNA-Polymerase II induction in mouse bone marrow-derived macrophages of two types: (a) untreated and (b) stimulated with lipopolysaccharide and interferon gamma to produce an inflammatory response.

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Diet-induced obesity dysregulates rapid epigenetic response to hypoxia in macrophages (ChIP-Seq)

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