Monocyte Enhancers are Highly Altered in Systemic Lupus Erythematosus

Shi, Lei; Zhang, Zhe; Song, Li; Leung, Yiu Tak; Petri, Michelle; Sullivan, Kathleen E.

doi:10.2217/epi.15.47

Cited by 27 publications

(21 citation statements)

References 65 publications

(56 reference statements)

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“…Shi et al [38] have shown that both promoters and enhancers exhibit significant changes in monocytes from SLE patients when compared with healthy controls. In particular, differentially methylated regions in SLE were significantly enriched in potential interferon-related TFBS.…”

Section: Discussionmentioning

confidence: 99%

Chromatin landscapes and genetic risk in systemic lupus

et al. 2016

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BackgroundSystemic lupus erythematosus (SLE) is a multi-system, complex disease in which the environment interacts with inherited genes to produce broad phenotypes with inter-individual variability. Of 46 single nucleotide polymorphisms (SNPs) shown to confer genetic risk for SLE in recent genome-wide association studies, 30 lie within noncoding regions of the human genome. We therefore sought to identify and describe the functional elements (aside from genes) located within these regions of interest.MethodsWe used chromatin immunoprecipitation followed by sequencing to identify epigenetic marks associated with enhancer function in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest. We also interrogated available data in Roadmap Epigenomics for CD4+ T cells and CD19+ B cells to identify these same elements in lymphoid cells.ResultsAll three cell types demonstrated enrichment of enhancer-associated histone marks compared with genomic background within LD blocks encoded by SLE-associated SNPs. In addition, within the promoter regions of these LD blocks, all three cell types demonstrated enrichment for transcription factor binding sites above genomic background. In CD19+ B cells, all but one of the LD blocks of interest were also enriched for enhancer-associated histone marks.ConclusionsMuch of the genetic risk for SLE lies within or near genomic regions of disease-relevant cells that are enriched for epigenetic marks associated with enhancer function. Elucidating the specific roles of these noncoding elements within these cell-type-specific genomes will be crucial to our understanding of SLE pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1169-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Chromatin landscapes and genetic risk in systemic lupus

et al. 2016

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“…They were purified by elutriation and adherence and were more than 90% pure by flow cytometry. The SLE samples reported in Figure 1 were obtained as part of a previously reported study under a separate IRB-approved protocol [33, 34]. MonoMac6 cells were used as a monocyte cell line, and K562 was used as an early hematopoietic stem cell line.…”

Section: 0 Materials and Methodsmentioning

confidence: 99%

“…HEK293 cells were cultured in DMEM with 10% cosmic calf serum and were obtained from ATCC and thawed fresh for these experiments. The SLE patient RNA samples have been previously reported [3, 33], although these analyses are new. Transfection of cells was performed by electroporation with the Amaxa Cell Line Lonza Nucleofector Kit (Amaxa Biosystems, Gaithersburg, MD) or Lipofectamine 2000 (ThermoFisher, Waltham, MA).…”

Section: 0 Materials and Methodsmentioning

confidence: 99%

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SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs

Shii

Song

Maurer

et al. 2017

Molecular Immunology

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The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream enhancer RNAs upregulated SERPINB2 and the enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF. Stimulation with LPS led to recruitment of the pause-releasing kinase P-TEFb and departure of the pause-inducing protein NELF. RNA immunoprecipitation revealed that NELF and the CDK9 component of P-TEFb bound to the enhancer RNAs after stimulation with distinct kinetics. Knock-down of the enhancer RNAs compromised stimulus induction of promoter and enhancer chromatin changes. Conversely, over-expression was associated with enhanced recruitment of c-JUN and increased expression of SERPINB2 mRNA expression. This study is the first to associate enhancer RNAs with SERPINB2 and is the first demonstration of acquisition of NELF binding by enhancer RNAs on chromatin.

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“…It will be very interesting to study how changes in the epigenome associate with disease. It was recently shown that monocytes isolated from patients with systemic lupus erythematosus (SLE) show clear changes in their enhancer landscape and that these changes particularly occur in regions associated with interferon responses, a critical hallmark of the inflammatory profile in SLE and a target for intervention in this disease (115). It is expected that many research programs will focus on comprehensive mapping of the epigenome in human disease to better understand disease development and possibly to identify specific epigenetic markers for disease, disease stages, and effectiveness of interventions.…”

Section: Therapeutics and Future Perspectivesmentioning

confidence: 99%