Circles of Life: linking metabolic and epigenetic cycles to immunity

Abstract

Metabolites are the essential substrates for epigenetic modification enzymes to write or erase the epigenetic blueprint in cells. Hence, the availability of nutrients and activity of metabolic pathways strongly influence the enzymatic function. Recent studies have shed light on the choreography between metabolome and epigenome in the control of immune cell differentiation and function, with a major focus on histone modifications. Yet, despite its importance in gene regulation, DNA methylation and its relationship with metabolism is relatively unclear. In this review, we will describe how the metabolic flux can influence epigenetic networks in innate and adaptive immune cells, with a focus on the DNA methylation cycle and the metabolites S-adenosylmethionine and α-ketoglutarate. Future directions will be discussed for this rapidly emerging field.

Keywords: 5-hydroxymethylcytosine; B cells; DNA methylation; DNA methyltransferases; Krebs cycle; T cells; epigenetics; immunometabolism; macrophages; mitochondria; one-carbon metabolism; ten-eleven translocation.

Figure 1

Metabolic pathways that provide metabolic substrates for epigenetic cycle. Glycolysis (orange), involves the enzymatic catabolism of glucose to pyruvate and lactate in the cytoplasm. Pyruvate can be converted to acetyl‐CoA in mitochondria and shuttled through several enzymatic reactions of the Krebs cycle (gray) to generate metabolic intermediates. Glutamine through glutaminolysis (purple) can be metabolized to α‐ketoglutarate in the Krebs cycle. Intermediates from glucose catabolism during glycolysis can branch out through the serine one‐carbon metabolism (blue) to generate amino acids of serine and glycine fueling into the folate and methionine cycle to generate S‐adenosyl‐methionine. 3PG, 3‐phosphoglycerate; 3PHP, 3‐phosphohydroxypyruvate; 3PS, 3‐phosphoserine; PHGDH, phosphoglycerate dehydrogenase; PSAT1, phosphoserine aminotransferase 1; PSPH, phosphoserine phosphatase; MAT, methionine adenosyltransferase; SAM, S‐adenosyl‐methionine; MT, methyltransferase; SAH, S‐adenosylhomocysteine; HCY, homocysteine; AHCY, S‐adenosylhomocysteine hydrolase; αKG, α‐ketoglutarate; KGDH, α‐ketoglutarate dehydrogenase

Figure 2

The DNA methylation cycle. In the mammalian genome, the majority of the cytosines at CG motifs are methylated. DNA methyltransferases (DNMTs) catalyze the addition of a methyl group to the fifth carbon of cytosine (C), generating 5‐methylcytosine (5mC). TETs then convert 5mC into oxidized methylcytosines (oxi‐mCs): 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxylcytosine (5caC). While TETs are capable of the complete oxidization of 5mC to 5caC in vitro, the majority of oxi‐mCs in the cells are 5hmC. 5hmC is stable and a potential epigenetic mark. 5fC and 5caC are unstable and are removed by TDG (thymine DNA glycosylase) with the base‐excision repair. The base removal process (red arrows) constitutes ‘active DNA demethylation’. During DNA replication, the pairing between newly synthesized DNA with the original modified CpG motif creates the hemi‐modified CpG. The maintenance DNA methyltransferase complex DNMT1/UHRF1 recognizes the hemi‐methylated CpG and methylates the unmodified cytosine on the new DNA. However, DNMT1/UHRF1 cannot recognize the hemi‐methylated CpG containing oxi‐mCs, preventing the methylation of the newly synthesized DNA. Therefore, the methylation pattern will be erased after rounds of DNA replication

Figure 3

The intersection between metabolic cycles and DNA methylation cycle. (a) DNMT and methionine cycle. To methylate cytosine, DNMT uses S‐adenosyl methionine (SAM) as the methyl group donor, producing S‐adenosylhomocysteine (SAH) as a result. SAH is then recycled back to the methionine cycle (Fig. 1), regenerating SAM for additional methylation. (b) TET and Krebs cycle. With reduced iron (Fe²⁺) as a co‐factor, TET converts the substrates 5mC, α‐ketoglutarate (αKG), and oxygen into the products 5hmC, succinate, and carbon dioxide. TET can further oxidize 5hmC into 5fC and 5caC (not depicted). Succinate can be shuttled back to the Krebs cycle and regenerating αKG. Additional αKG can be derived from glutamine via glutaminolysis (Fig. 1).