Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming

Abstract

Epigenetic modifications on DNA and histones regulate gene expression by modulating chromatin accessibility to transcription machinery. Here we identify methionine as a key nutrient affecting epigenetic reprogramming in CD4 + T helper (Th) cells. Using metabolomics, we showed that methionine is rapidly taken up by activated T cells and serves as the major substrate for biosynthesis of the universal methyl donor S-adenosyl-L-methionine (SAM). Methionine was required to maintain intracellular SAM pools in T cells. Methionine restriction reduced histone H3K4 methylation (H3K4me3) at the promoter regions of key genes involved in Th17 cell proliferation and cytokine production. Applied to the mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), dietary methionine restriction reduced the expansion of pathogenic Th17 cells in vivo, leading to reduced T cell-mediated neuroinflammation and disease onset. Our data identify methionine as a key nutritional factor shaping Th cell proliferation and function in part through regulation of histone methylation.

Methio “mine”! Cancer cells steal methionine and impair CD8 T‐cell function

“…Indeed, metabolomics studies performed by Bian and colleagues confirmed dramatically decreased intracellular methionine and SAM levels upon methionine starvation 3 . This is in line with recent studies, which described a rapid turnover and a reduction of up to 98% of the SAM pool within hours of starving cells of methionine 8,9 . Being the methyl donor for various methyltransferases, SAM concentrations directly affect the levels of H3K79me2, an active gene mark in mammalian cells.…”

“…In mammals, methionine is essential for de novo protein synthesis and required for the production of S‐adenosylmethionine (SAM), a universal methyl donor required for DNA and RNA methylation and substrate for multiple histone and protein methyltransferases. Thereby, SAM links nutrient availability and cellular metabolism directly with epigenetic regulation 8,9 . Indeed, metabolomics studies performed by Bian and colleagues confirmed dramatically decreased intracellular methionine and SAM levels upon methionine starvation 3 .…”

“…Using a transwell system with varying methionine concentrations, the authors further showed that tumor cells outcompeted the T cells for methionine. Although methionine can also be generated de novo in mammalian cells, recent studies have shown that T cells are dependent on methionine uptake via the system L transporter Solute Carrier Family 7 Member 5 (SLC7A5) 8,9 . Unlike T cells, which only express SLC7A5, tumor cells in addition express high amounts of a second system L transporter, namely, SLC43A2.…”

Proteome overabundance enables respiration but limitation onsets carbon overflow

“…The model predicted different underlying mechanisms causing the nutrient-responsive carbon overflow compared with the growth rate-dependent carbon overflow ( Figure 4B, S1B, S4B). It suggested that nitrogen limitation besides activating pathways related to nitrogen metabolism also activated the tetrahydrofolate (THF) cycle (C1 metabolism) affecting folate and methionine biosynthesis together with the precursor metabolite pathways (serine, chorismate) which important as these changes are reported to influence mitochondrial dynamics and play an important role in cancer metabolism ( Figure 4B, S1B, S4A) (Gao et al, 2018;Roy et al, 2020). The activation of these pathways led to not just C2 overflow (ethanol) but also C1 overflow (formate) under nitrogen limitation which we validated by measuring formate in culture samples ( Figure 4B, S1B, S4A).…”

Effects of High- and Low-proteindiets on Inflammatory Profiles in People With Morbid Obesity: A 3-week Intervention Study

“…High-protein diets were particularly suggested to modulate in ammatory concentrations in patients with obesity and diabetes (15), and in the ageing population (16,17). On the other hand, a low-protein diet especially low-methionine diet was shown to bene cially in uence glucose intolerance (18) and modulate immune-in ammatory state (19,20).…”