The Transcriptional Repressor cAMP Response Element Modulator α Interacts with Histone Deacetylase 1 to Repress Promoter Activity

Tenbrock, Klaus; Juang, Yuang-Taung; Leukert, Nadja; Roth, Johannes; Tsokos, George C.

doi:10.4049/jimmunol.177.9.6159

Cited by 60 publications

(42 citation statements)

References 26 publications

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“…In addition to its transactivating or trans-repressing effects on promoters, CREMα also mediates epigenetic remodeling of IL2 through the recruitment of DNMT3a (8) and HDAC1 (8,16,17). These findings are in line with recent reports on the transcription factor B-cell maturation protein (Blimp-)1.…”

Section: Discussionsupporting

confidence: 80%

“…T cells from SLE patients express increased levels of CREMα, resulting in epigenetic remodeling of cytokine genes, including IL2 (8,10,13,16,17). We hypothesized that CREMα recruits de novo DNA methyltransferases to the IL2 promoter mediating epigenetic remodeling of IL2 in T cells from SLE patients (8).…”

Section: Resultsmentioning

confidence: 99%

“…T cells from SLE patients are characterized by severe signaling anomalies resulting in altered cytokine production (14). CREMα has been linked to reduced IL-2 and increased IL-17A expression through diametric trans-regulatory effects on the IL2 and IL17A genes (8,(15)(16)(17). CREMα expression is controlled by trans-activation and trans-repression of the CREM promoter P1 (9,10).…”

Section: Inflammation | Gene Regulationmentioning

confidence: 99%

“…These findings may reflect dose-dependent effects of CREMα on both the IL2 and IL17A promoters. Data from our group suggest that CREMα could primarily mediate trans-activating effects on the IL2 promoter at low levels and epigenetic remodeling in active disease (8,12,16,17). In the case of IL17A, CREMα could mediate active demethylation or inhibit (re)methylation of the promoter, whereas higher doses may be necessary for transactivation (15).…”

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confidence: 99%

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cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

Hedrich

Crispín

Rauen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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119

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Appropriate expression of IL-2 plays a central role during the priming and differentiation of T cells. A tight balance between IL-2 and the effector cytokine IL-17A is essential for immune homeostasis. Epigenetic mechanisms have been documented as a key component of cytokine regulation during lineage commitment. The molecular mechanisms that induce chromatin remodeling are less well understood. We investigated epigenetic regulators that mediate the diametric expression of IL-2 and IL-17A in naive, central memory, and effector memory CD4 + T cells. We demonstrate that cAMP response modulator (CREM)α contributes to epigenetic remodeling of IL2 in effector memory T cells through the recruitment of DNMT3a. CREMα also reduces CpG-DNA methylation of the IL17A promoter. CREMα expression is regulated at the epigenetic level by CpG-DNA methylation, which allows increased CREMα expression in effector memory CD4 + T cells. T cells from patients with systemic lupus erythematosus (SLE) express increased levels of CREMα and exhibit a phenotype that is similar to effector memory CD4 + T cells with epigenetically predetermined expression patterns of IL-2 and IL-17A. We conclude that CREMα mediates epigenetic remodeling of the IL2 and IL17A gene during T-cell differentiation in favor of effector memory T cells in health and disease.inflammation | gene regulation

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Inflammation | Gene Regulationmentioning

confidence: 99%

mentioning

confidence: 99%

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cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

Hedrich

Crispín

Rauen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

119

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“…The regulatory regions of some genes known to be involved in the disease's pathogenesis (for example ITGAL, CD40LG, CD70, and PPP2CA) have been reported to be hypomethylated in SLE [22].…”

Section: Epigenetic Effectsmentioning

confidence: 99%

Proteomic analysis of human plasma and peripheral blood mononuclear cells in Systemic Lupus Erythematosus patients

Pinna

Pasella

Deiana³

et al. 2017

Journal of Immunological Methods

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CREMα suppresses spleen tyrosine kinase expression in normal but not systemic lupus erythematosus T cells

Ghosh¹,

Kis-Tóth²,

Juang³

et al. 2012

Arthritis & Rheumatism

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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 cAMP response element modulator (CREM) α which suppresses the production of interleukin-2. Because SYK expression can be suppressed by CREM α we asked why CREM α fails to suppress SYK expression in SLE T cells. Methods Healthy T cells were overexpressed with CREM α expression vector and SYK expression and phosphorylation was measured. A newly identified CRE site on SYK promoter was characterized by ChIP and EMSA. The CREM α-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 the CREM α binding and histone-H3 acetylation. Results We demonstrate that increased CREM α level can suppress SYK expression by direct binding on a CRE site of the SYK promoter in T cells from healthy individuals but failed to do so in SLE T cells. We demonstrate that failure of CREM α to suppress SYK expression in SLE T cells is due to weaker binding to the CRE site of the SYK promoter compared to healthy T cells because the promoter site is hypoacetylatylated and therefore of limited access to transcription factors. Conclusions Epigenetic alteration of the SYK promoter in SLE T cells results in inability of the transcriptional repressor CREM α to bind and suppress the expression of SYK resulting in aberrant T cell signaling.

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The Transcriptional Repressor cAMP Response Element Modulator α Interacts with Histone Deacetylase 1 to Repress Promoter Activity

Cited by 60 publications

References 26 publications

cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

Proteomic analysis of human plasma and peripheral blood mononuclear cells in Systemic Lupus Erythematosus patients

CREMα suppresses spleen tyrosine kinase expression in normal but not systemic lupus erythematosus T cells

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