title: Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus.
abstract: Up-regulated cyclic adenosine 5'-monophosphate response element modulator α (CREMα) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). This research aimed to investigate the mechanisms regulating CREMα expression in SLE.
  
  
  
  From the chromatin immunoprecipitation (ChIP) microarray data, we found a sharply increased H3 lysine 4 trimethylation (H3K4me3) amount at the CREMα promoter in SLE CD4+ T cells compared to controls. Then, by ChIP and real-time PCR, we confirmed this result. Moreover, H3K4me3 amount at the promoter was positively correlated with CREMα mRNA level in SLE CD4+ T cells. In addition, a striking increase was observed in SET domain containing 1 (Set1) enrichment, but no marked change in mixed-lineage leukemia 1 (MLL1) enrichment at the CREMα promoter in SLE CD4+ T cells. We also proved Set1 enrichment was positively correlated with both H3K4me3 amount at the CREMα promoter and CREMα mRNA level in SLE CD4+ T cells. Knocking down Set1 with siRNA in SLE CD4+ T cells decreased Set1 and H3K4me3 enrichments, and elevated the levels of DNMT3a and DNA methylation, while the amounts of H3 acetylation (H3ac) and H4 acetylation (H4ac) didn't alter greatly at the CREMα promoter. All these changes inhibited the expression of CREMα, then augmented IL-2 and down-modulated IL-17A productions. Subsequently, we observed that DNA methyltransferase (DNMT) 3a enrichment at the CREMα promoter was down-regulated significantly in SLE CD4+ T cells, and H3K4me3 amount was negatively correlated with both DNA methylation level and DNMT3a enrichment at the CREMα promoter in SLE CD4+ T cells.
  
  
  
  In SLE CD4+ T cells, increased Set1 enrichment up-regulates H3K4me3 amount at the CREMα promoter, which antagonizes DNMT3a and suppresses DNA methylation within this region. All these factors induce CREMα overexpression, consequently result in IL-2 under-expression and IL-17A overproduction, and contribute to SLE at last. Our findings provide a novel approach in SLE treatment.
authors.affiliation: Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
authors.forename: Shu
authors.initials: S
authors.lastname: Ding
authors.affiliation: Emergency Department, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
authors.forename: Hai
authors.initials: H
authors.lastname: Long
authors.affiliation: Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Vera
authors.initials: V
authors.lastname: Chan
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chak-Sing
authors.initials: CS
authors.lastname: Lau
authors.affiliation: Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011 China.
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C497410:CREM protein, human; C000717967:DNMT3A protein, human; D006657:Histones; C508717:IL17A protein, human; C508594:IL2 protein, human; D020381:Interleukin-17; D007376:Interleukin-2; D051786:Cyclic AMP Response Element Modulator; D000090205:DNA Methyltransferase 3A; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human
keywords: CREMα; DNA methylation; DNMT3a; H3K4me3; Set1; Systemic lupus erythematosus