Journal article
Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis
The Journal of clinical investigation, Vol.120(9), pp.3209-3219
09/01/2010
DOI: 10.1172/JCI40034
PMCID: PMC2929711
PMID: 20714105
Abstract
Antineutrophil cytoplasmic autoantibody (ANCA) causes vascular injury that leads to small-vessel vasculitis. Patients with ANCA aberrantly express neutrophil granule-encoding genes, including 2 that encode autoantigens: proteinase 3 (PR3) and myeloperoxidase (MPO). To uncover a potential transcriptional regulatory mechanism for PR3 and MPO disrupted in patients with ANCA vasculitis, we examined the PR3 and MPO loci in neutrophils from ANCA patients and healthy control individuals for epigenetic modifications associated with gene silencing. We found that levels of the chromatin modification H3K27me3, which is associated with gene silencing, were depleted at PR3 and MPO loci in ANCA patients compared with healthy controls. Interestingly, in both patients and controls, DNA was unmethylated at a CpG island in PR3, whereas in healthy controls, DNA was methylated at a CpG island in MPO. Consistent with decreased levels of H3K27me3, JMJD3, the demethylase specific for H3K27me3, was preferentially expressed in ANCA patients versus healthy controls. In addition, we describe a mechanism for recruiting the H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) to PR3 and MPO loci mediated by RUNX3. RUNX3 message was decreased in patients compared with healthy controls, and may also be under epigenetic control. DNA methylation was increased at the RUNX3 promoter in ANCA patients. These data indicate that epigenetic modifications associated with gene silencing are perturbed at ANCA autoantigen-encoding genes, potentially contributing to inappropriate expression of PR3 and MPO in ANCA patients.
Details
- Title: Subtitle
- Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis
- Creators
- Dominic J. Ciavatta - University of North Carolina at Chapel HillJiaJin Yang - Univ N Carolina, Div Nephrol & Hypertens, UNC Kidney Ctr, Chapel Hill, NC 27599 USAGloria A. Preston - University of North CarolinaAnshul K. Badhwar - University of North CarolinaHong Xiao - Emory University HospitalPeter Hewins - University Hospitals Birmingham NHS Foundation TrustCarla M. Nester - University of IowaWilliam F. Pendergraft - NephrologyTerry R. Magnuson - Lineberger Comprehensive Cancer CenterJ. Charles Jennette - Emory University HospitalRonald J. Falk - Nephrology
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.120(9), pp.3209-3219
- DOI
- 10.1172/JCI40034
- PMID
- 20714105
- PMCID
- PMC2929711
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 11
- Grant note
- P01DK058335 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) PO1 DK058335 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 09/01/2010
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984354047602771
Metrics
14 Record Views