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Inhibition of EZH2 in THP-1 cells

ABSTRACT: Macrophages play a key role in both innate and adaptive immunity, but our knowledge on the changes in transcription regulation that occurs during their differentiation from monocytes is still limited. In this study, we used a meta-analysis followed by a systems biology approach for the identification of differentially expressed genes between monocytes and macrophages and possible regulators of these changes in transcription. Based on the pattern of gene expression change, transcription regulator analysis predicted a decrease in Enhancer of Zeste homolog 2 (EZH2), a histone 3 lysine 27 methyl transferase, activity after differentiation of monocytes into macrophages. This inhibition was validated by a significant decrease in trimethylated H3K27 during differentiation of both human primary monocytes into macrophages and the THP-1 cell line into macrophage-like cells. Overexpressing EZH2 during differentiation of monocytes and THP-1 cells obstructs cellular adhesion, thus preventing the first step in differentiation. Another facet of macrophage differentiation is the cessation of proliferation, and inhibition of EZH2 by the small molecule inhibitor GSK126 in THP-1 cells indeed impedes proliferation. This study shows an important part for epigenetic changes during monocyte differentiation. It highlights the role of EZH2 activity behind the changes needed in adhesion and proliferation mechanisms for macrophage formation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71671 | GEO | 2015/08/04

SECONDARY ACCESSION(S): PRJNA291772

REPOSITORIES: GEO

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Project description:Macrophages play a critical role in the pathogenesis of many diseases, including rheumatoid arthritis, inflammatory bowel disease and atherosclerosis. Monocytes recruited into tissues from peripheral blood differentiate into macrophages. There is limited data concerning the global changes in the expression of genes during monocyte to macrophage, and how the patterns of change identify the mechanism contributing to differentiation or macrophage function. Employing the microarray technology, we examined the transcriptional profile of in vitro adherence-induced differentiation of primary human monocytes into macrophages. We found the significant up regulation of genes contributing to the functions of macrophage, including signature patterns defining the induction of genes contributing to immunity and defense; lipid, fatty acid and steroid metabolism; cell adhesion and; carbohydrate metabolism; amino acid metabolism and endocytosis. In contrast, a variety of transcription factors were down regulated during monocyte to macrophage differentiation, suggesting that transcriptional repression may be important for the transition from monocytes to macrophages. However, a limited number of transcription factors were up regulated, among these was C/EBPA, which may contribute to differentiation by regulating down stream genes, which a characteristic of differentiated macrophages. These observations suggest that examination of the transcriptional profile in monocytes and macrophages in patients may identify relevant therapeutic targets in diseases such as rheumatoid arthritis and atherosclerosis. Experiment Overall Design: Total 9 samples were analyzed. Repeats of 3 total RNA samples from monocytes at 0 hour, 3 samples from monocytes at 16 hours, and other 3 samples of monocytes at 168 hours after differentiation were collected. Following the Affymetrix protocol, 5-10 mg of high quality RNA was used to make labeled cRNA. The size distribution of fragmented and unfragmented labeled cRNA were assessed by 2100 Bioanalyzer (Agilent Technologies). 20mg of fragmented labeled cRNA was hybridized to Human U133A GeneChip at 45C for 18 hours. Affymetrix fluidics station was used to perform the washing and staining of the chips. GeneChip 3000 scanner system was used to scan the chips. The data were normalized by dCHIP method.

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Inhibition of EZH2 in THP-1 cells

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