Understanding and mitigating the role of epigenetics (environmental influences that trigger changes in gene expression) in disease development is a major goal of researchers. Now, a newly published paper featured on the March cover of the journal Brain adds significantly to this work by detailing how metabolites can be used to inhibit epigenetic mechanisms and effectively treat a range of diseases, including multiple sclerosis (MS). Dimethyl fumarate (Tecfidera™; a cell-permeable derivative of the metabolite fumaric acid) is an approved treatment for MS and is potentially an effective therapy for other autoimmune diseases. The precise mechanism of the drug’s action has been only partially understood. Until now, scientists know that this molecule inside cells becomes reactive, leading to activation of a transcription factor called Nrf-2. Once active, Nrf-2 induces a specific pattern of gene expression with antioxidant proteins (Trx-1, Trx-2, Prx-1) and antioxidant enzymes (GSR, TxR1, SOD2, HO-1, ecc.). This way cells can buffer the oxidative stress subsequent to the disease. However, scientists suspect further mechanisms of action.
In their new paper, researchers at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York and the Icahn School of Medicine at Mount Sinai take a major step toward unraveling the mystery by identifying other possible mechanism for fumaric acid derivatives. In doing so, they also highlight new concepts that may lay the groundwork for the development of novel classes of drugs for the treatment of MS and other diseases. Scientists believe that MS develops when epigenetic changes cause certain brain-homing immune cells (or T lymphocytes) to attack the central nervous system. In their current study researchers, led by Patrizia Casaccia, director of the ASRC Neuroscience Initiative and a professor of Genetics and Neuroscience at Mount Sinai, posited that fumaric metabolites work by mitigating the development of certain brain-homing T cells. Researchers recruited 97 volunteers with MS that were either treatment-naïve (47), fumaric-treated (35), or glatiramer acetate-treated (16).
Blood samples were collected from each participant and their levels of brain-homing T cells were measured by looking at the percentages of the chemokine receptors CCR4 and CCR6, which are critical to T cell trafficking between the gut, brain, and skin. The data showed significantly lower levels of these brain-homing T cells in the Tecfidera-treated group than in the other comparison groups. Researchers subsequently analyzed how these molecules change the epigenetic landscape of T cells to reduce the development of these pathogenic cells. Specifically, they found that fumaric derivatives have a strong epigenetic effect (hypermethylation) on a particular DNA region in T cells that includes a microRNA called miR-21, which is necessary to create disease-associated brain-homing T cells. Taken together, the results suggest that the immune-modulatory effect of fumaric metabolites in MS is at least in part due to the epigenetic regulation of these specific brain-homing T cells. Anyway, no other details in molecular mechanisms were explored though it is recognized that succinic acid may change DNA methylation, at least in cancer cells.
The enzyme succinate dehydrogenase (SDH) oxidizes succinate into fumarate in citric acid cycle (Krebs cycle). However, to exert DNA methylation-promoting activity, fumarate must firstly be converted into succinate. Since SDH operates the inverse reaction, some cellular reductases should first transform fumarate into succinate. There is currently no knowledge of such mechanism in nervous cells or in immune cells. However, very recently scientists reported that another Krebs metabolite was found to act on redox mechanisms linked with anti-inflammatory pathways, itaconate. His 4-octyl-derivative activates Nrf-2 transcription factor to enhance antioxidant gene expression, while suppressing cytokine production in immune cells like macrophages. Achilles Ntranos, MD, first author of the paper, concluded: “We first demonstrate that Krebs cycle intermediates, such as fumaric acid esters, have a significantly higher impact on epigenome-wide DNA methylation changes in CD4 T cells compared to glatiramer acetate. Our findings about therapeutically active metabolites have implications for the treatment of not only multiple sclerosis, but also other autoimmune diseases such as psoriasis and inflammatory bowel disease, which involve the same type of T cells”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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