title: cAMP-responsive element modulator (CREM)α protein signaling mediates epigenetic remodeling of the human interleukin-2 gene: implications in systemic lupus erythematosus.
abstract: IL-2 is a key cytokine during proliferation and activation of T lymphocytes and functions as an auto- and paracrine growth factor. Regardless of activating effects on T lymphocytes, the absence of IL-2 has been linked to the development of autoimmune pathology in mice and humans. Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease and characterized by dysregulation of lymphocyte function, transcription factor and cytokine expression, and antigen presentation. Reduced IL-2 expression is a hallmark of SLE T lymphocytes and results in decreased numbers of regulatory T lymphocytes which play an important role in preventing autoimmunity. Reduced IL-2 expression was linked to overproduction of the transcription regulatory factor cAMP-responsive element modulator (CREM)α in SLE T lymphocytes and subsequent CREMα binding to a CRE site within the IL2 promoter (-180 CRE). In this study, we demonstrate the involvement of CREMα-mediated IL2 silencing in T lymphocytes from SLE patients through a gene-wide histone deacetylase 1-directed deacetylation of histone H3K18 and DNA methyltransferase 3a-directed cytosine phosphate guanosine (CpG)-DNA hypermethylation. For the first time, we provide direct evidence that CREMα mediates silencing of the IL2 gene in SLE T cells though histone deacetylation and CpG-DNA methylation.
authors: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA. chedrich@bidmc.harvard.edu
authors: Christian M
authors: CM
authors: Hedrich
authors: Thomas
authors: T
authors: Rauen
authors: George C
authors: GC
authors: Tsokos
mesh_terms: D000107:Acetylation; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007376:Interleukin-2 / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D006657:Histones; D007376:Interleukin-2; D051786:Cyclic AMP Response Element Modulator; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A