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

Clinical Epigenetics, Dec 2016

Background 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. Results 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. Conclusions 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.

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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

Zhang et al. Clinical Epigenetics 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 Qing Zhang 0 Shu Ding 2 Huilin Zhang 1 Hai Long 0 Haijing Wu 0 Ming Zhao 0 Vera Chan 3 Chak-Sing Lau 3 Qianjin Lu 0 0 Department of Dermatology, Second Xiangya Hospital, Central South University , Changsha, Hunan 410011 , China 1 Emergency Department, Second Xiangya Hospital, Central South University , Changsha, Hunan 410011 , China 2 Department of Dermatology, Third Xiangya Hospital, Central South University , Changsha, Hunan 410011 , China 3 Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong , Hong Kong , China Background: 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. Results: 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. Conclusions: 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. Systemic lupus erythematosus; CREMα; H3K4me3; Set1; DNA methylation; DNMT3a - Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which multiple pathogenic mechanisms are involved in [1, 2]. Recently, accumulating studies have documented that epigenetic alterations in certain genes of T cells play critical roles in the pathogenesis of SLE [3, 4]. Epigenetics refers to heritable changes in gene expression without changes in the DNA sequence [5, 6]. The epigenetic mechanisms include mainly DNA methylation, histone modifications, noncoding RNA regulation, and chromatin modifications [5, 7]. It has been proved that DNA methylation is hallmark of gene silencing [8], while H3 lysine 4 trimethylation (H3K4me3), H3 acetylation (H3ac), and H4 acetylation (H4ac) are all correlated with transcriptional activation [9–11]. As one of the most familiar histone modifications, H3K4me3 is always a focus of epigenetics. It accumulates predominantly at the promoters and early transcribed regions of active genes, and is involved in transcription initiation, elongation and RNA processing by interacting with RNA polymerase II [12, 13]. It also can recruit and/or stabilize chromatin-remodeling enzymes and transcriptional cofactors [14, 15]. Interestingly, H3K4me3 is able to inhibit DNA methylation by antagonizing DNA methyltransferase (DNMT) 3a [16], and augment histone acetylation by interacting with histone acetyltransferases (HATs) [17]. As we all know, histone methyltransferases (HMTs) SET domain containing 1 (Set1) and mixed-lineage leukemia 1 (MLL1) can both catalyze trimethylation of H3K4 [18, 19]. Set1 and MLL1 are both large proteins containing one C-terminal SET domain that is associated with an intrinsic histone lysine-specific methyltransferase activity [20–22]. They are present, respectively, as the catalytic subunit and central element of multi-protein H3K4 methyltransferase complexes named complex of proteins associated with Set1 (COMPASS) and COMPASS-like [23–25]. Besides the catalytic Set1/MLL1 subunit, COMPASS/COMPASS-like contains several oth (...truncated)


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Qing Zhang, Shu Ding, Huilin Zhang, Hai Long, Haijing Wu, Ming Zhao, Vera Chan, Chak-Sing Lau, Qianjin Lu. 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, Clinical Epigenetics, 2016, pp. 126, Volume 8, Issue 1, DOI: 10.1186/s13148-016-0294-2