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Longitudinal analysis of mRNA transcripts and plasma proteins to define a biomarker associated with lupus disease activity

Arthritis Research & Therapy
Springer (Biomed Central Ltd.)
Publication Date
DOI: 10.1186/ar3937
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ARTV14S3 1..28 MEETING ABSTRACTS Open Access Lupus 2012: New targets, new approaches Whistler, Canada. 27-30 September 2012 Edited by Peter E Lipsky, John M Esdaile, Matthew H Liang and Paul R Fortin Published: 27 September 2012 These abstracts are available online at MEETING ABSTRACTS A1 Epigenetics and lupus B Richardson University of Michigan, Ann Arbor, MI, USA Arthritis Research & Therapy 2012, 14(Suppl 3):A1 Lupus develops when genetically predisposed people encounter environmental agents that initiate flares. Current evidence indicates that the environmental contribution is mediated by T-cell DNA demethylation. DNA methylation patterns are established during differentiation, and silence inappropriate or unnecessary genes by promoting a condensed chromatin configuration that is inaccessible to transcription factors. The methylation patterns are then replicated each time a cell divides by DNA methyltransferase 1 (Dnmt1). Dnmt1 is upregulated during mitosis, binds the replication fork, and catalyzes transfer of the methyl group from S-adenosylmethionine (SAM) to dC bases in the daughter DNA strand only where the parent strand is methylated. Environmental agents that block ERK pathway signaling prevent Dnmt1 upregulation, and low Dnmt1 levels synergize with dietary micronutrient deficiencies that decrease SAM pools to impair methylation of the daughter strand. This activates genes silenced only by DNA methylation. Inhibiting T-cell DNA methylation converts helper CD4+ T cells into autoreactive, cytotoxic, proinflammatory cells that cause lupus-like autoimmunity in mice. Similar changes in CD4+ T-cell DNA methylation and gene expression are found in patients with active lupus. Procainamide and hydralazine, which cause ANAs in a majority of patients and lupus in a genetically predisposed subset, also inhibit T-cell DNA methylation. The lupus T-cell DNA methylation defect has been traced to low Dnmt1 levels caused by decreased ERK path

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