Unknown,Transcriptomics,Genomics,Proteomics

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Tiling path analysis of Drosophila Schneider 2 cultured cells to map forum domains

ABSTRACT: Forum domains are stretches of chromosomal DNA that are excised from eukaryotic chromosomes during their spontaneous non-random fragmentation. Mostly forum domains are of 50-200 kb in length, although larger domains, up to 500 - 700 kb, are also observed.

We performed a genome-wide mapping of forum domains termini in Drosophila Schneider 2 cultured cells using Drosophila melanogaster genomic tiling microarray consisting of overlapping 3 kb fragments. We found that forum domains contain clusters of several or many genes inside. The largest forum domains correspond to the coordinately expressed main clusters of homeotic genes inside BX-C and ANTP-C, cluster of histone genes and clusters of piRNAs. PRE/TRE and binding sites of transcription factors are often reside inside domains, and do not overlap with forum domains termini. The terminal regions of domains often correspond to chromosomal sites containing different classes of mobile elements, binding sites of SuUR protein and regions of intercalary heterochromatin. Our results indicate that forum domains correspond to big multi-gene chromosomal units some of which could be co-coordinately activated or repressed.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Nickolai Tchurikov

PROVIDER: E-MEXP-2468 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Progression and relapse-free survival of ovarian carcinoma are associated with the abundance of immunosuppressed CD163highCD206high tumor-associated macrophages (TAMs) and high levels of polyunsaturated fatty acids (PUFAs), in particular arachidonic acid (AA), in the tumor microenvironment. In the present study, we have investigated whether both associations are functionally linked. Methods: The effect of PUFAs on cytokine-mediated pro-inflammatory signal transduction was studied in primary monocyte-derived macrophages (MDMs) by transcriptomics, bioinformatics, phosphoprotein analysis of signal transduction proteins and MS-based proteomics of lipid rafts. Results: Pathway analysis of transcriptional profiles revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signal transduction. This is mirrored by an impairment of the transcriptional response to interferon-beta (IFNbeta), IFNgamma and IL-6 in monocyte-derived macrophages (MDMs) by AA. This AA-mediated inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, as indicated by the inhibition by PUFAs of JAK1, JAK2, STAT1 and STAT3 phosphorylation, with the strongest inhibitory effects exerted by AA and its non-metabolizable analog ETYA. AA/ETYA treatment of MDMs results in altered composition of lipid rafts, including reduced amounts of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins. The AA-mediated inhibition of IFN-triggered STAT1 phosphorylation was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by PUFAs. Conclusion: Our data suggest that AA, and to a lesser degree other PUFAs, impair pro-inflammatory signaling in macrophages, at least in part by altering the structure of lipid rafts, and thereby contribute to the reeducation of tumor-associated macrophages. Our findings also suggest that the pharmacologic restoration of lipid raft functions in TAM may be a promising strategy for the development of new therapeutic approaches.

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Tiling path analysis of Drosophila Schneider 2 cultured cells to map forum domains

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