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: Christian M Hedrich, Thomas Rauen, George C Tsokos
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 50 Pg. 43429-36 (Dec 16 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21976679 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNMT3A protein, human
• Dnmt3a protein, mouse
• Histones
• Interleukin-2
• Cyclic AMP Response Element Modulator
• DNA (Cytosine-5-)-Methyltransferases
• DNA Methyltransferase 3A

Topics

• Acetylation
• Cell Line
• Chromatin Immunoprecipitation
• Computational Biology
• Cyclic AMP Response Element Modulator (genetics, metabolism)
• DNA (Cytosine-5-)-Methyltransferases (genetics, metabolism)
• DNA Methylation (genetics)
• DNA Methyltransferase 3A
• Epigenesis, Genetic (genetics)
• Histones (metabolism)
• Humans
• Immunoprecipitation
• Interleukin-2 (genetics)
• Lupus Erythematosus, Systemic (genetics, metabolism)
• Protein Binding
• T-Lymphocytes (metabolism)