Dataset Information


Selective modulation of inflammatory Natural Killer (NK) cell phenotypes following histone H3K27 demethylase inhibition [RNA-Seq]

ABSTRACT: Natural Killer cells are innate lymphocytes, participate in immune surveillance and elimination of stressed or transformed cells and critically shape the inflammatory cytokine environment to interact with cells of the innate and adaptive immune system, including macrophages, dendritic and Tcells. By performing a focused compound library screening, further validated by knockdown approaches, we here identify Jumonji-type histone 3 lysine 27 (H3K27) demethylases as key regulators of cytokine production in various human NK cell subsets. The prototypic H3K27 demethylase inhibitor GSK-J4 increases global levels of the repressive H3K27me3 mark around transcription start sites including NK cell effector cytokines, and thereby reduces IFN-γ, TNFα, GM-CSF and IL-10 levels in IL-15 stimulated NK cells whilst sparing the cytotoxic killing capacity against cancer cells. The anti-inflammatory effect of GSK-J4 in highly inflammatory NK cell subsets, isolated from peripheral blood or tissue from rheumatoid arthritis patients, coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggests a wider role and utility of histone demethylase inhibition in immunity and inflammation. Overall design: We constructed 6 RNA-seq libraries; two conditions in triplicate. NK cells were cultured in media in the presence of IL-15 stimulation then cultured in the presence of DMSO and GSK-J4 treated NK cells. RNA was collected at 24 hours.

INSTRUMENT(S): Illumina NextSeq 500 (Homo sapiens)

SUBMITTER: Adam Cribbs  

PROVIDER: GSE89484 | GEO | 2018-02-28


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Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells.

Cribbs Adam A   Hookway Edward S ES   Wells Graham G   Lindow Morten M   Obad Susanna S   Oerum Henrik H   Prinjha Rab K RK   Athanasou Nick N   Sowman Aneka A   Philpott Martin M   Penn Henry H   Soderstrom Kalle K   Feldmann Marc M   Oppermann Udo U  

The Journal of biological chemistry 20180104 7

Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule in  ...[more]

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