p300 Protein Acetyltransferase Activity Suppresses Systemic Lupus Erythematosus-Like Autoimmune Disease in Mice

Forster, Nicole; Gallinat, Sven; Jabłońska, Jadwiga; Weiß, Siegfried; Elsässer, Hans–Peter; Lutz, W

doi:10.4049/jimmunol.178.11.6941

Cited by 43 publications

(27 citation statements)

References 56 publications

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“…This likely stems from decreased histone acetyltransferase activity, resulting in impaired acetylation and decreased transcription of the miR-150 host gene (97). A B cell-specific conditional knock-in dominant negative p300 acetyltransferase mutant results in the production of class-switched anti-dsDNA autoantibodies and the development of lupus-like traits in C57BL/6 129Sv F1 mice (105). By contrast, increased expression of certain miRNAs may contribute to the development of autoimmunity, as suggested by increased numbers of germinal center B cells in the spleen and peripheral lymph nodes in miR-17-92 transgenic mice (17) upon silencing of miR-21 (106).…”

Section: Dysregulation Of Mirna In Lupusmentioning

confidence: 99%

MicroRNAs in lupus

2014

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of an array of pathogenic autoantibodies, including high-affinity anti-dsDNA IgG antibodies, which plays an important role in disease development and progression. Lupus preferentially affects women during their reproductive years. The pathogenesis of lupus is contributed by both genetic factors and epigenetic modifications that arise from exposure to the environment. Epigenetic marks, including DNA methylation, histone post-translational modifications and microRNAs (miRNAs), interact with genetic programs to regulate immune responses. Epigenetic modifications influence gene expression and modulate B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses to exogenous antigens or self-antigens, such as chromatin, histones and dsDNA in lupus. miRNAs play key roles in the post-transcriptional regulation of most gene-regulatory pathways and regulate both the innate and the adaptive immune responses. In mice, dysregulation of miRNAs leads to aberrant immune responses and development of systemic autoimmunity. Altered miRNA expression has been reported in human autoimmune diseases, including lupus. The dysregulation of miRNAs in lupus could be the result of multiple environmental factors, such as sex hormones and viral or bacterial infection. Modulation of miRNA is a potential therapeutic strategy for lupus.

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Section: Dysregulation Of Mirna In Lupusmentioning

confidence: 99%

MicroRNAs in lupus

2014

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“…Acetylation by histone acetylases (HATs) eliminates the charge differences between histones and DNA allowing transcription factors to access DNA [79]. The expression of the HAT p300 is protective against lupus and its loss results in a SLE phenotype in mice [80]. HATs utilize acetyl-CoA for acetylation reactions.…”

Section: Histone Modificationsmentioning

confidence: 99%

Metabolic control of the epigenome in systemic Lupus erythematosus

Oaks

Perl

2013

Autoimmunity

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Epigenetic mechanisms are proposed to underlie aberrant gene expression in systemic lupus erythematosus (SLE) that results in dysregulation of the immune system and loss of tolerance. Modifications of DNA and histones require substrates derived from diet and intermediary metabolism. DNA and histone methyltransferases depend on S-adenosylmethionine (SAM) as a methyl donor. SAM is generated from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase (MAT), a redox-sensitive enzyme in the SAM cycle. The availability of B vitamins and methionine regulate SAM generation. The DNA of SLE patients is hypomethylated, indicating dysfunction in the SAM cycle and methyltransferase activity. Acetyl-CoA, which is necessary for histone acetylation, is generated from citrate produced in mitochondria. Mitochondria are also responsible for de novo synthesis of flavin adenine dinucleotide (FAD) for histone demethylation. Mitochondrial oxidative phosphorylation is the dominant source of ATP. The depletion of ATP in lupus T cells may affect MAT activity as well as adenosine monophosphate (AMP) activated protein kinase (AMPK), which phosphorylates histones and inhibits mechanistic target of rapamycin (mTOR). In turn, mTOR can modify epigenetic pathways including methylation, demethylation, and histone phosphorylation and mediates enhanced T-cell activation in SLE. Beyond their role in metabolism, mitochondria are the main source of reactive oxygen intermediates (ROI), which activate mTOR and regulate the activity of histone and DNA modifying enzymes. In this review we will focus on the sources of metabolites required for epigenetic regulation and how the flux of the underlying metabolic pathways affects gene expression.

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“…The acetyltrans-ferase activity of p300 in B cells is crucial in preventing autoimmunity. Mice with a B cell-specific knock-in mutant version of p300 that lacks only histone acetyl-transferase activity develop a lupus-like autoimmune disease characterized by splenomegaly, nephritis, and vasculitis [80]. Reduced global levels of H3K9me3 and histone 3 acetylation have been reported in lupus CD4+ T cells, and differences in the activity of histone acetyl-transferases have been observed in lupus CD4+ T cells [72].…”

Section: Variable Histone Protein Modification In Lupusmentioning

confidence: 99%

The role of epigenetic variation in the pathogenesis of systemic lupus erythematosus

Hughes

Sawalha

2011

Arthritis Res Ther

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The focus of the present review is on the extent to which epigenetic alterations influence the development of systemic lupus erythematosus. Lupus is a systemic autoimmune disease characterized by the production of autoantibodies directed at nuclear self-antigens. A DNA methylation defect in CD4+ T cells has long been observed in idiopathic and drug-induced lupus. Recent studies utilizing high-throughput technologies have further characterized the nature of the DNA methylation defect in lupus CD4+ T cells. Emerging evidence in the literature is revealing an increasingly interconnected network of epigenetic dysregulation in lupus. Recent reports describe variable expression of a number of regulatory microRNAs in lupus CD4+ T cells, some of which govern the expression of DNA methyltransferase 1. While studies to date have revealed a significant role for epigenetic defects in the pathogenesis of lupus, the causal nature of epigenetic variation in lupus remains elusive. Future longitudinal epigenetic studies in lupus are therefore needed.

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p300 Protein Acetyltransferase Activity Suppresses Systemic Lupus Erythematosus-Like Autoimmune Disease in Mice

Cited by 43 publications

References 56 publications

MicroRNAs in lupus

MicroRNAs in lupus

Metabolic control of the epigenome in systemic Lupus erythematosus

The role of epigenetic variation in the pathogenesis of systemic lupus erythematosus

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