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Ezh2 loss is associated with functional defects and ectopic gene expression in mature neutrophils

ABSTRACT: Gene expression profiling of progenitor and neutrophil-derived HoxB8-ER cells (WT and Ezh2-/-) and neutrophil-derived HOXB8-ER treated with GSK343 and vehicle for 9 days. Ezh2 loss might lead to effective cytopenias caused by dysfunctional mature cells. To test this hypothesis, we examined Ezh2-null murine myeloid cell lines capable of neutrophilic differentiation. Bone marrow cells from Ezh2-/- and controls were immortalized with a HoxB8-estrogen receptor fusion and could be differentiated into mature neutrophils by removing estrogen from the culture medium.Gene expression profiling showed upregulation of oxidative phosphorylation pathway genes and ectopic expression of Gata1 and its associated erythroid gene targets. Functional and gene expression differences observed in Ezh2-/- derived neutrophils could be replicated in controls by treatment with the Ezh2-specific inhibitor GSK343. In conclusion, we demonstrate that Ezh2 loss allows for differentiation of normal appearing, but dysfunctional mature neutrophils characterized by ectopic gene expression and elevated levels of reactive oxygen species. These defects could contribute to the inflammatory bone marrow microenvironment and clinical phenotypes observed in patients with MDS.

ORGANISM(S): Mus musculus

PROVIDER: GSE107061 | GEO | 2017/11/18

SECONDARY ACCESSION(S): PRJNA418947

REPOSITORIES: GEO

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