Genome-wide analysis of 5-hmC in the peripheral blood of systemic lupus erythematosus patients using an hMeDIP-chip

Sui,Weiguo; Tan,Qiupei; Yang,Ming; Yan,Qiang; Lin,Hua; Ou,Minglin; Xue,Wen; Chen,Jiejing; Zou,Tongxiang; Jing,Huanyun; Guo,Li; Cao,Cuihui; Sun,Yufeng; Cui,Zhenzhen; Dai,Yong

doi:10.3892/ijmm.2015.2149

Genome-wide analysis of 5-hmC in the peripheral blood of systemic lupus erythematosus patients using an hMeDIP-chip

Authors:
- Weiguo Sui
- Qiupei Tan
- Ming Yang
- Qiang Yan
- Hua Lin
- Minglin Ou
- Wen Xue
- Jiejing Chen
- Tongxiang Zou
- Huanyun Jing
- Li Guo
- Cuihui Cao
- Yufeng Sun
- Zhenzhen Cui
- Yong Dai
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Affiliations: Guangxi Key Laboratory of Metabolic Diseases Research, Central Laboratory of Guilin 181st Hospital, Guilin, Guangxi 541002, P.R. China, Clinical Medical Research Center, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, P.R. China
Published online on: March 19, 2015 https://doi.org/10.3892/ijmm.2015.2149
Pages: 1467-1479

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Abstract

Systemic lupus erythematosus (SLE) is a chronic, potentially fatal systemic autoimmune disease characterized by the production of autoantibodies against a wide range of self-antigens. To investigate the role of the 5-hmC DNA modification with regard to the onset of SLE, we compared the levels 5-hmC between SLE patients and normal controls. Whole blood was obtained from patients, and genomic DNA was extracted. Using the hMeDIP-chip analysis and validation by quantitative RT-PCR (RT-qPCR), we identified the differentially hydroxymethylated regions that are associated with SLE. There were 1,701 genes with signiﬁcantly different 5-hmC levels at the promoter region in the SLE patients compared with the normal controls. The CpG islands of 3,826 genes showed signiﬁcantly different 5-hmC levels in the SLE patients compared with the normal controls. Out of the differentially hydroxymethylated genes, three were selected for validation, including TREX1, CDKN1A and CDKN1B. The hydroxymethylation levels of the three genes were confirmed by RT-qPCR. The results suggested that there were significant alterations of 5-hmC in SLE patients. Thus, these differentially hydroxymethylated genes may contribute to the pathogenesis of SLE. These ﬁndings show the signiﬁcance of 5-hmC as a potential biomarker or promising target for epigenetic-based SLE therapies.

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1	Woodman I: Connective tissue diseases: The MECP2/IRAK1 locus modulates SLE risk via epigenetics. Nat Rev Rheumatol. 9:1972013.PubMed/NCBI
2	Baizabal-Carvallo JF, Alonso-Juarez M and Koslowski M: Chorea in systemic lupus erythematosus. J Clin Rheumatol. 17:69–72. 2011. View Article : Google Scholar : PubMed/NCBI
3	Ponticelli C, Glassock RJ and Moroni G: Induction and maintenance therapy in proliferative lupus nephritis. J Nephrol. 23:9–16. 2010.PubMed/NCBI
4	Thabet Y, Cañas F, Ghedira I, Youinou P, Mageed RA and Renaudineau Y: Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link? J Autoimmun. 39:154–160. 2012. View Article : Google Scholar : PubMed/NCBI
5	Sui W, Hou X, Che W, Yang M and Dai Y: The applied basic research of systemic lupus erythematosus based on the biological omics. Genes Immun. 14:133–146. 2013. View Article : Google Scholar : PubMed/NCBI
6	Tahiliani M, Koh KP, Shen Y, et al: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 324:930–935. 2009. View Article : Google Scholar : PubMed/NCBI
7	Huang Y, Pastor WA, Shen Y, Tahiliani M, Liu DR and Rao A: The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS One. 5:e88882010. View Article : Google Scholar : PubMed/NCBI
8	Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC and Zhang Y: Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 466:1129–1133. 2010. View Article : Google Scholar : PubMed/NCBI
9	Yamaguchi S, Hong K, Liu R, et al: Dynamics of 5-methylcytosine and 5-hydroxymethylcytosine during germ cell reprogramming. Cell Res. 23:329–339. 2013. View Article : Google Scholar : PubMed/NCBI
10	Jin SG, Kadam S and Pfeifer GP: Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Res. 38:e1252010. View Article : Google Scholar : PubMed/NCBI
11	Wu SC and Zhang Y: Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol. 11:607–620. 2010. View Article : Google Scholar : PubMed/NCBI
12	Williams K, Christensen J and Helin K: DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep. 13:28–35. 2011. View Article : Google Scholar : PubMed/NCBI
13	Song CX, Yi C and He C: Mapping recently identified nucleotide variants in the genome and transcriptome. Nat Biotechnol. 30:1107–1116. 2012. View Article : Google Scholar : PubMed/NCBI
14	Stroud H, Feng S, Morey Kinney S, Pradhan S and Jacobsen SE: 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol. 12:R542011. View Article : Google Scholar : PubMed/NCBI
15	Xu Y, Wu F, Tan L, et al: Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell. 42:451–464. 2011. View Article : Google Scholar : PubMed/NCBI
16	Gao Y, Chen J, Li K, et al: Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell. 12:453–469. 2013. View Article : Google Scholar : PubMed/NCBI
17	Thomson JP, Lempiäinen H, Hackett JA, et al: Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome. Genome Biol. 13:R932012. View Article : Google Scholar : PubMed/NCBI
18	Guo JU, Su Y, Zhong C, Ming GL and Song H: Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 145:423–434. 2011. View Article : Google Scholar : PubMed/NCBI
19	Sironi M, Biasin M, Forni D, et al: Genetic variability at the TREX1 locus is not associated with natural resistance to HIV-1 infection. AIDS. 26:1443–1445. 2012. View Article : Google Scholar : PubMed/NCBI
20	Hur JW, Sung YK, Shin HD, Cheong HS and Bae SC: TREX1 polymorphisms associated with autoantibodies in patients with systemic lupus erythematosus. Rheumatol Int. 28:783–789. 2008. View Article : Google Scholar
21	Lee-Kirsch MA, Gong M, Chowdhury D, et al: Mutations in the gene encoding the 3′–5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 39:1065–1067. 2007. View Article : Google Scholar : PubMed/NCBI
22	O’Driscoll M: TREX1 DNA exonuclease deficiency, accumulation of single stranded DNA and complex human genetic disorders. DNA Repair. 7:997–1003. 2008. View Article : Google Scholar : PubMed/NCBI
23	Kavanagh D, Spitzer D, Kothari PH, et al: New roles for the major human 3′–5′ exonuclease TREX1 in human disease. Cell Cycle. 7:1718–1725. 2008. View Article : Google Scholar : PubMed/NCBI
24	Pulliero A, Marengo B, Domenicotti C, et al: Inhibition of neuroblastoma cell growth by TREX1-mutated human lymphocytes. Oncol Rep. 27:1689–1694. 2012.PubMed/NCBI
25	Namjou B, Kothari PH, Kelly JA, et al: Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 12:270–279. 2011. View Article : Google Scholar : PubMed/NCBI
26	Kim K, Sung YK, Kang CP, Choi CB, Kang C and Bae SC: A regulatory SNP at position -899 in CDKN1A is associated with systemic lupus erythematosus and lupus nephritis. Genes Immun. 10:482–486. 2009. View Article : Google Scholar : PubMed/NCBI
27	Miyagawa H, Yamai M, Sakaguchi D, et al: Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus. Rheumatology. 47:158–164. 2008. View Article : Google Scholar : PubMed/NCBI
28	Yang W, Tang H, Zhang Y, et al: Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am J Hum Genet. 92:41–51. 2013. View Article : Google Scholar : PubMed/NCBI