Presentation: Abnormal Histone Modification Patterns in Lupus CD4+ T Cells (2007)

841 Abnormal Histone Modification Patterns in Lupus CD4+ T Cells

Purpose: Epigenetic factors have been implicated in aging and in the pathogenesis of human disease such as cancer and autoimmunity. We have recently demonstrated that global and gene-specific DNA methylation changes are involved in systemic lupus erythematosus (SLE). Herein, we described for the first time alterations in global histone H3/H4 methylation/acetylation status in lupus CD4+ T cells. Moreover, we determined the expression of twelve members of three classes of chromatin modifier genes CD4+ T cells from lupus patients.
Methods: Twenty SLE patients were recruited and disease activity was assessed using the SLE Disease Activity Index (SLEDAI). CD4+ T cells from twenty SLE patients and ten healthy controls were isolated by positive selection using Miltenyi beads. Histone extraction and detection of global histone H3/H4 acetylation and H3K4/H3K9 methylation were performed using the EpiQuik™ Global Histone H3/H4 Acetylation Assay Kit or EpiQuik™ Global Histone H3-K4/H3-K9 Methylation Assay Kit (Epigentek ). Quantitative real-time RT-PCR was used to examine the mRNA expression of twelve members of three classes of chromatin modifier genes including histone acetyltransferases (HATs)-EP300, CREBBP and PCAF, histone deacetylases (HDACs)-HDAC1, HDAC2, HDAC4, HDAC5, HDAC7 and SIRT1; and histone methyltransfeases (HMTs)- SUV39H1, SUV39H2 and EZH2.
Results: Ten out of twenty SLE patients had active disease with SLEDAI values of 9.8±4.9 [ mean±SD:9.8±4.9] compared to ten patients with inactive disease (SLEDAI:1.0±1.7 [mean±SD]). We found global histone H3 and H4 hypoacetylation in active lupus CD4+ T cells compared to controls (p=0.002 and p=0.009, respectively). There was a negative correlation between global histone H3 hypoacetylation and disease activity by SLEDAI (Pearson correlation= -0.901,p=0.037). In addition, we found global histone H3K9 hypomethylation in both active and inactive lupus CD4+ T cells compared to controls(p=0.001,p=0.001). However, global level of H3K4 methylation was not different between patients and controls (p>0.05). SIRT1 mRNA levels were significantly increased in CD4+T cells from active lupus patients compared to healthy controls (p=0.02). On the other hand, the mRNA levels of CREBBP, P300, HDAC2, HDAC7, SUV39H2 and EZH2 were significantly down-regulated in active lupus patients in comparison with normal controls (p=0.002, p=0.02, p=0.001, p=0.02, p=0.01, p=0.003, respectively). Conclusions: Our data indicate that both histone acetylation and histone methylation are abnormal in CD4+ T cells from active lupus patients. This aberrancy in histone codes might play an important role in the pathogenesis of SLE.
Supported by the National Natural Science Foundation of China (No 30671883)

 N. Hu, None; X. Qiu, None; Y. Luo, None; J. Yuan, None; W. Lei, None; X. Yang, None; Y. Li, None; G. Zhang, None; Y. Zhou, None; Y. Su, None; Q. Lu, None.