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Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the spontaneous canine model of non-Hodgkin lymphoma [ATAC-seq]

ABSTRACT: Targeting PRMT5 in canine lymphoma: we characterized expression patterns of PRMT5 in canine lymphomas and correlated these with histological subtypes using tissue microarrays. We characterized expression of PRMT5 in three canine lymphoma-derived cell lines and primary lymph node biopsies. We have demonstrated that inhibition of PRMT5 leads to growth suppression and induction of apoptosis in canine lymphoma cell lines and primary canine lymphoma cells in a time and dose-dependent manner, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric di-methylation. We performed ATAC-sequencing with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility after PRMT5 inhibition. We performed gene expression microarrays with pathway analysis to characterize whole transcriptome changes in canine lymphoma cell lines treated with PRMT5 inhibitors. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued used of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE156084 | GEO | 2021/04/20

REPOSITORIES: GEO

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Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the spontaneous canine model of non-Hodgkin lymphoma [array]

Project description:Targeting PRMT5 in canine lymphoma: we characterized expression patterns of PRMT5 in canine lymphomas and correlated these with histological subtypes using tissue microarrays. We characterized expression of PRMT5 in three canine lymphoma-derived cell lines and primary lymph node biopsies. We have demonstrated that inhibition of PRMT5 leads to growth suppression and induction of apoptosis in canine lymphoma cell lines and primary canine lymphoma cells in a time and dose-dependent manner, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric di-methylation. We performed ATAC-sequencing with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility after PRMT5 inhibition. We performed gene expression microarrays with pathway analysis to characterize whole transcriptome changes in canine lymphoma cell lines treated with PRMT5 inhibitors. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued used of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.

2021-04-20 | GSE155599 | GEO

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Project description:Post-translational arginine methylation is responsible for regulation of a variety of biological processes. The protein arginine methyltransferase 5 (PRMT5) is the major enzyme responsible for generating monomethyl- and symmetric dimethyl arginine (MMA and SDMA, respectively) in proteins. PRMT5 is essential for viability and normal development, and overexpressed in a wide variety of cancer types. In the present study, we found that the levels of PRMT5 and symmetric dimethylation in proteins from colorectal cancer (CRC) tissues are more highly maintained relative to adjacent normal tissues from patients. Using immunoaffinity enrichment of methylated peptides combined with high resolution mass spectrometry, a total of 147 SDMA sites from 94 proteins were identified. Most abundant methylated proteins identified from normal and CRC tissues are RNA processing proteins, transcriptional and translational regulators. Furthermore, when quantitative analysis of the two tissue types of samples was carried out, 77 SDMA sites exhibited statistically significant changes (>2.0-fold, p-value <0.05) between normal and CRC tissues. We confirmed KSRP, G3BP2 and TRIP6 which are more highly maintained in cancer tissues relative to adjacent normal tissues from same patients as well as the expression levels of the proteins. This study is the first comprehensive analysis of symmetric arginine dimethylation using clinical samples and suggests that the modification can be used in clinical application.

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Binding of guide piRNA triggers methylation of the unstructured N-terminal region of Aub leading to assembly of the piRNA amplification complex

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