Yang Jiajin, Ge Heng, Poulton Caroline J, Hogan Susan L, Hu Yichun, Jones Britta E, Henderson Candace D, McInnis Elizabeth A, Pendergraft William F, Jennette J Charles, Falk Ronald J, Ciavatta Dominic J
UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Xian Jiaotong University, 157 Xiwu Road, Xian, Shaanxi 710004 People's Republic of China.
Clin Epigenetics. 2016 Aug 12;8:85. doi: 10.1186/s13148-016-0251-0. eCollection 2016.
Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by destructive vascular inflammation. Two prominent ANCA autoantigens are myeloperoxidase (MPO) and proteinase 3 (PR3), and transcription of and , the genes encoding the autoantigens, is associated with disease activity. We investigated whether patients with AAV have alterations in histone modifications, particularly those associated with transcriptional activation, at and .
We identified a network of genes regulating histone modifications that were differentially expressed in AAV patients compared to healthy controls. We focused on four genes ( and , , and ) and found their expression correlated with expression of and . Methylation of histone H3K9, catalyzed by EHMT1 and EHMT2 and associated with gene silencing, was most depleted at and in patients with active disease and the highest and expression. Acetylation of histone H4K16, modified by complexes containing ING4 and MSL1 and associated with gene activation, was most enriched at and in patients with active disease and the highest and expression. Methylation at H3K4, a mark of transcriptional activation, was enriched at and in patients and healthy controls.
and in neutrophils of AAV patients with active disease have a distinct pattern of histone modifications, which implicates epigenetic mechanisms in regulating expression of autoantigen genes and suggests that the epigenome may be involved in AAV pathogenesis.
抗中性粒细胞胞浆自身抗体（ANCA）相关血管炎（AAV）是一种以破坏性血管炎症为特征的系统性自身免疫性疾病。两种主要的ANCA自身抗原是髓过氧化物酶（MPO）和蛋白酶3（PR3），编码这些自身抗原的基因和的转录与疾病活动相关。我们研究了AAV患者在和处的组蛋白修饰是否存在改变，特别是那些与转录激活相关的修饰。
我们鉴定出一个调节组蛋白修饰的基因网络，与健康对照相比，该网络在AAV患者中差异表达。我们聚焦于四个基因（和、、和），发现它们的表达与和的表达相关。由EHMT1和EHMT2催化并与基因沉默相关的组蛋白H3K9甲基化，在疾病活动期且和表达最高的患者中，在和处最为减少。由包含ING4和MSL1的复合物修饰并与基因激活相关的组蛋白H4K16乙酰化，在疾病活动期且和表达最高的患者中，在和处最为富集。作为转录激活标志的H3K4甲基化，在患者和健康对照的和处均有富集。
疾病活动期AAV患者中性粒细胞中的和具有独特的组蛋白修饰模式，这暗示表观遗传机制在调节自身抗原基因表达中起作用，并表明表观基因组可能参与AAV的发病机制。
