Metabolic control of the epigenome in systemic Lupus erythematosus

Abstract

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.

Environmental exposures and the development of systemic lupus erythematosus

“…Studies in syngeneic mice have shown that injecting demethylated DNA into CD4+ T cells with can precipitate a lupus-like syndrome(39, 40). The role of underlying metabolic mechanisms in modifying gene expression in SLE is also proposed (41). Oxidative stress likely also contributes to SLE pathogenesis, and has been shown to inhibit ERK pathway signaling in T cells leading to DNA demethylation, upregulation of immune genes and autoreactivity (42*).…”

Epigenetic dynamics in immunity and autoimmunity

“…Mitochondria are the dominant source of ATP. Mitochondrial dysfunction and ATP depletion have been reported in lupus CD4 + T cells, which inhibits the mTOR pathway and modifies epigenetic pathways, including methylation, demethylation, and histone phosphorylation, and mediates enhanced T cell activation in SLE (Oaks and Perl, 2014). Therefore, metabolic control of epigenetic dynamics may play a leading role in the pathogenesis of SLE.…”

Sucrose non-fermenting AMPK related kinase/Pentraxin 3 and DNA damage axis: a gateway to cardiovascular disease in systemic lupus erythematosus among Egyptian patients

“…1 SLE patients have elevated concentrations of pro-inflammatory cytokines such as IL-6, TNF-a and IL-1 which contribute to the inflammatoryprocess. 2 Cardiovascular disease (CVD) risk is at least doubled among SLE patients compared with the general population.…”