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Transcriptomic analysis of fumarate compounds identifies unique effects of isosorbide di-(methyl fumarate) on NRF2, NF-kappaB and IRF1 pathway genes

ABSTRACT: Dimethyl fumarate (DMF) has emerged as first-line therapy for relapsing-remitting multiple scle-rosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared effects of fumarates on gene expression in astrocytes. Our analysis included diroximel fumarate (DRF) and its metabolite monomethyl fumarate (MMF), along with a novel compound isosorbide di-(methyl fumarate) (IDMF). Treatment with IDMF resulted in the largest number of differentially expressed genes. The effects of DRF and MMF were consistent with NRF2 activation and NF-kappaB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-kappaB inhibition, and we confirmed IDMF-mediated NF-kappaB inhibition using a reporter assay. IDMF also down-regulated IRF1 expression and IDMF-decreased gene promoters were enriched with IRF1 recognition se-quences. Genes altered by each fumarate overlapped significantly with those near loci from MS genetic association studies, but IDMF had the strongest overall effect on MS-associated genes. These results show that next-generation fumarates such as DRF and IDMF have effects differing from those of the MMF metabolite. Our findings support a model in which IDMF attenuates oxidative stress via NRF2 activation, with suppression of NF-kappaB and IRF1 contributing to mitigation of in-flammation and pyroptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200539 | GEO | 2022/04/27

REPOSITORIES: GEO

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Transcriptomic analysis of fumarate compounds identifies unique effects of isosorbide di-(methyl fumarate) on NRF2, NF-kappaB and IRF1 pathway genes

Project description:Transcriptomic analysis of fumarate compounds identifies unique effects of isosorbide di-(methyl fumarate) on NRF2, NF-kappaB and IRF1 pathway genes

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A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [RNA-seq]

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Project description:Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth and survival. Understanding these mechanisms and developing biomarkers to identify their presence thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of the covalent targets of fumarate, an oncometabolite whose accumulation marks the genetic cancer predisposition syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). First, we validate the ability of known and novel chemoproteomic probes to report on concentration-dependent fumarate reactivity in vitro. Next, we apply these probes in concert with LC-MS/MS to identify cysteine residues sensitive to either fumarate treatment or fumarate hydratase (FH) mutation in untransformed and HLRCC cell models, respectively. Mining this data to understand the structural determinants of fumarate reactivity led to the discovery of an unexpected anti-correlation with nucleophilicity, indicating a novel influence of pH on fumarate-cysteine interactions. Finally, we show that many fumarate-sensitive and FH-regulated cysteines are found in functional protein domains, and perform functional studies of a fumarate-sensitive cysteine in SMARCC1 that lies at a key protein-protein interface in the SWI-SNF tumor suppressor complex. Our studies provide a powerful resource for understanding the influence of fumarate on reactive cysteine residues, and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.

2018-11-27 | PXD009378 | Pride

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