cAMP-responsive element modulator (CREM)α protein induces interleukin 17A expression and mediates epigenetic alterations at the interleukin-17A gene locus in patients with systemic lupus erythematosus.
IL-17A is a proinflammatory cytokine that is produced by specialized T helper cells and contributes to the development of several autoimmune diseases such as systemic lupus erythematosus (SLE). Transcription factor cAMP-responsive element modulator (CREM)α displays increased expression levels in T cells from SLE patients and has been described to account for aberrant T cell function in SLE pathogenesis. In this report, we provide evidence that CREMα physically binds to a cAMP-responsive element, CRE (-111/-104), within the proximal human IL17A promoter and increases its activity. Chromatin immunoprecipitation assays reveal that activated naïve CD4(+) T cells as well as T cells from SLE patients display increased CREMα binding to this site compared with T cells from healthy controls. The histone H3 modification pattern at the CRE site (-111/-104) and neighboring conserved noncoding sequences within the human IL17A gene locus suggests an accessible chromatin structure (H3K27 hypomethylation/H3K18 hyperacetylation) in activated naïve CD4(+) T cells and SLE T cells. H3K27 hypomethylation is accompanied by decreased cytosine phosphate guanosine (CpG)-DNA methylation in these regions in SLE T cells. Decreased recruitment of histone deacetylase (HDAC)1 and DNA methyltransferase (DNMT)3a to the CRE site (-111/-104) probably accounts for the observed epigenetic alterations. Reporter studies confirmed that DNA methylation of the IL17A promoter indeed abrogates its inducibility. Our findings demonstrate an extended role for CREMα in the immunopathogenesis of SLE because it contributes to increased expression of IL-17A.
Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA. trauen@bidmc.harvard.edu
Thomas
T
Rauen
Christian M
CM
Hedrich
Yuang-Taung
YT
Juang
Klaus
K
Tenbrock
George C
GC
Tsokos
D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D024202:Electrophoretic Mobility Shift Assay; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
C000717967:DNMT3A protein, human; D006657:Histones; D020381:Interleukin-17; D051786:Cyclic AMP Response Element Modulator; D000090205:DNA Methyltransferase 3A