title: CREMα suppresses spleen tyrosine kinase expression in normal but not systemic lupus erythematosus T cells.
abstract: OBJECTIVE
  T cells from patients with systemic lupus erythematosus (SLE) display increased amounts of spleen tyrosine kinase (Syk), which is involved in the aberrant CD3/T cell receptor-mediated signaling process, and increased amounts of CREMα, which suppresses the production of interleukin-2. Syk expression can be suppressed by CREMα. This study was undertaken to investigate why CREMα fails to suppress Syk expression in SLE T cells.
  
  
  METHODS
  CREMα was overexpressed in healthy T cells by transfection with CREMα expression vector, and Syk expression and phosphorylation were measured. A newly identified cAMP response element (CRE) site on the SYK promoter was characterized by chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay. The CREMα-mediated repression of Syk expression was further evaluated by analyzing SYK promoter activity. T cells from SLE patients and healthy individuals were subjected to ChIP to evaluate CREMα binding and histone H3 acetylation.
  
  
  RESULTS
  Increased CREMα levels suppressed Syk expression by direct binding to a CRE site of the SYK promoter in T cells from healthy individuals but failed to do so in T cells from SLE patients. The failure of CREMα to suppress Syk expression in SLE T cells was due to weaker binding to the CRE site of the SYK promoter compared to healthy T cells because the promoter site is hypoacetylated in SLE T cells and therefore of limited access to transcription factors.
  
  
  CONCLUSIONS
  Our findings indicate that epigenetic alteration of the SYK promoter in SLE T cells results in the inability of the transcriptional repressor CREMα to bind and suppress the expression of Syk, resulting in aberrant T cell signaling.
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Debjani
authors.initials: D
authors.lastname: Ghosh
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Toth
authors.forename: Yuang-Taung
authors.initials: YT
authors.lastname: Juang
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D001483:Base Sequence; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D051786:Cyclic AMP Response Element Modulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology*; D013601:T-Lymphocytes / Q000378:metabolism*; D014162:Transfection
chemical_list: D002843:Chromatin; D006657:Histones; D051786:Cyclic AMP Response Element Modulator; D000123:Acetyltransferases; D011505:Protein-Tyrosine Kinases