Table 1 |.
Regulation of gene expression by metabolites and metabolic enzymes
| Metabolite or enzyme | Regulation of gene expression | Mechanism | Links to disease |
|---|---|---|---|
| Metabolites | |||
| SAM | Histone methylation-dependent genes↑↓ | Methyl donor for methyltransferases | NA |
| FAD | Histone methylation-dependent genes↑↓ | Positive regulator of LSD1 and LSD2 | NA |
| α-KG | • HIF1-targeted genes↓ • Histone methylation-dependent genes↑↓ |
Cofactor for α-KG-utilizing dioxygenases | NA |
| Succinate | • HIF1-targeted genes↓ • Histone methylation-dependent genes↑↓ |
Inhibition of α-KG-utilizing dioxygenases | NA |
| Fumarate | • HIF1-targeted genes↑ • ATF2-targeted genes↑ • NRF2-targeted genes↑ • Histone methylation-dependent genes↑↓ |
• Inhibition of α-KG-utilizing dioxygenases • Activation of NRF2 |
NA |
| 2-HG | • HIF1-targeted genes↑ • Histone methylation-dependent genes↑↓ |
Inhibition of α-KG-utilizing dioxygenases | NA |
| Acetyl-CoA | • HIF2-targeted genes↑ • TFEB-targeted genes↑ • Memory-related neuronal genes↑ • Glucose metabolism-related genes↑ • Cell cycle progression-related genes↑ • AhR-targeted genes↑ • Other histone acetylation-dependent genes↑ |
Acetyl donor for acetyltransferases | NA |
| NAD+ | • SIRT-regulated and histone acetylation-dependent genes↓ • Genes regulated by PARylation of histones and transcription regulators (CLOCK, NELFA, NELFE and KDM5B)↑↓ |
Activation of histone deacetylase (SIRT) and PARP | NA |
| NAM, β-hydroxybutyrate and butyrate | Histone acetylation-dependent genes↑ | Inhibition of histone deacetylase | NA |
| Succinyl-CoA | Regulation of more than 7,000 genes↑↓ | Histone succinylation | NA |
| Metabolic enzymes | |||
| PKM2 | • CCND1↑ • MYC↑ • STAT3-targeted genes (MEK5)↑ • HIF1-targeted genes↑ • AhR-targeted genes↑ • OCT4-targeted genes↓ |
• Phosphorylation of H3T11 • Activation of β-catenin, STAT3, HIF1 and AhR • Suppression of OCT4 |
Tumour development |
| ACSS2 | • HIF2-targeted genes↑ • TFEB-targeted genes↑ • Memory-related neuronal genes↑ |
Histone acetylation | • Anaemia • Tumour development • Memory disorder |
| ACLY | Glucose metabolism-related genes↑ | Histone acetylation | Tumour development |
| PDC | • Cell cycle progression-related genes↑ • AhR-targeted genes↑ |
Histone acetylation | ND |
| FH | • HIF1-targeted genes↑a • ATF2-targeted genes↑a • NRF2-targeted genes↑a • Histone methylation-dependent genes↑↓a |
• Inhibition of α-KG-utilizing dioxygenases • Activation of NRF2 |
Tumour development associated with FH loss of function |
| SDH, IDH1 and IDH2 mutants | • HIF1-targeted genes↑a • Histone methylation-dependent genes↑↓a |
Inhibition of α-KG-utilizing dioxygenases | • Tumour development associated with loss of function of the SDHgenes • Tumour development associated with IDH1 and/or IDH2 mutation |
| FBP1 | HIF1-targeted genes↓ | Binding and inhibiting HIF1α and HIF2α | Tumour development associated with FBP1 genomic loci loss |
| PFKFB4 | ATF4-targeted genes↑ | Stabilizing the recruitment of SRC3 and ATF4 to target gene promoters | Tumour growth and metastasis |
| GAPDH | H2B gene↑ | Recruitment to the H2B promoter | ND |
| α-KGDH | Regulation of more than 7,000 genes↑↓ | Histone succinylation | ND |
| IMPDH | Histone genes and E2F genes↓ | Binding to single-stranded CT-rich DNA elements | ND |
| GMPS | • PRC1 and PRC2-regulated homeotic genes↓ • Ecdysone-inducible genes↓ |
Deubiquitylation of p53 and histone H2B | ND |
| MATII | • HMOX1 gene↓ • Histone methylation-regulated genes↑↓ |
Histone methylation | ND |
α-KG, α-ketoglutarate; α-KGDH, α-KG dehydrogenase; ACLY, ATP citrate synthase; ACSS2, acetyl-CoA synthetase short-chain family member 2; AhR, aryl hydrocarbon receptor; ATF, activating transcription factor; CLOCK, circadian locomotor output cycles protein kaput; FBP1, fructose-1,6-bisphosphatase 1; FH, fumarase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GMPS, GMP synthase; H3T11, histone H3 threonine 11; HIF, hypoxia-inducible factor; IDH, isocitrate dehydrogenase; IMPDH, inosine 5′-monophosphate dehydrogenase; KDM5B, lysine-specific demethylase 5B; LSD, lysine-specific histone demethylase; MATII, methionine adenosyltransferase II; NA, not applicable; NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; ND, not determined; NELF, negative elongation factor; NRF2, nuclear factor erythroid 2-related factor 2; OCT4, octamer-binding protein 4; PDC, pyruvate dehydrogenase complex; PFKFB4, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4; PKM2, pyruvate kinase M2 isoform; PRC, Polycomb repressive complex; SAM, S-adenosylmethionine; SDH, succinate dehydrogenase; SIRT, sirtuin; SRC3, steroid receptor co-activator protein 3; STAT3, signal transducer and activator of transcription 3; TFEB, transcription factor EB.
Effects observed in mutants (FH and SDH loss of function and IDH1 and/or IDH2 mutants).