Chromatin as a key consumer in the metabolite economy

Abstract

In eukaryotes, chromatin remodeling and post-translational modifications (PTMs) shape the local chromatin landscape to establish permissive and repressive regions within the genome, orchestrating transcription, replication, and DNA repair in concert with other epigenetic mechanisms. Though cellular nutrient signaling encompasses a huge number of pathways, recent attention has turned to the hypothesis that the metabolic state of the cell is communicated to the genome through the type and concentration of metabolites in the nucleus that are cofactors for chromatin-modifying enzymes. Importantly, both epigenetic and metabolic dysregulation are hallmarks of a range of diseases, and this metabolism-chromatin axis may yield a well of new therapeutic targets. In this Perspective, we highlight emerging themes in the inter-regulation of the genome and metabolism via chromatin, including nonenzymatic histone modifications arising from chemically reactive metabolites, the expansion of PTM diversity from cofactor-promiscuous chromatin-modifying enzymes, and evidence for the existence and importance of subnucleocytoplasmic metabolite pools.

Figure 1.. Metabolites regulate chromatin modifications.

a) The concentration of cofactor with respect to K_M of the chromatin-modifying enzyme affects that enzyme’s activity. HAT = histone acetyltransferase, KDM = lysine demethylase, FAD = flavin adenine dinucleotide. b) Metabolites can be endogenous inhibitors of chromatin modifiers. PARP = poly-ADP-ribose polymerase, KDM = lysine demethylase, NAM = nicotinamide. c) Chromatin may serve as a storage depot for metabolic capacity. For example, acetyl-CoA can be stored as histone acetylation that is mobilized by the action of histone deacetylases and ACSS2. HAT = histone acetyltransferase, HDAC = histone deacetylase, ACSS2- acetyl-CoA synthetase short-chain family member 2.

Figure 2.. Non-enzymatic histone modifications.

a) Structures of histone acylations from the corresponding acyl-CoA. b) Oxidation of unsaturated fatty acids leads to reactive species that react with histone lysines. COX2 = cyclooxygenase 2. c) Methylglyoxyl (MGO) generated from glycolysis reacts with lysine and arginine residues, eventually leading to advanced glycation products (AGEs) that stimulate inflammatory pathways. DJ-1 = protein/nucleic acid deglycase DJ-1.

Figure 3.. Metabolic pathways that produce and interconvert acyl-CoAs involved in histone acylations.

Bold = enzyme, italics = pathway, ACLY = ATP citrate lyase, ACSS2 = Acyl-CoA synthetase short-chain family member 2, PDC = pyruvate dehydrogenase complex, TCA cycle = tricarboxylic acid cycle, CDYL = chromodomain Y-like transcription corepressor, MDC = malonyl-CoA decarboxylase, ACC = acetyl-coA carboxylase, SCAD = short-chain acyl-CoA dehydrogenase, GCDH = glutaryl-CoA dehydrogenase, PCC = propionyl-CoA carboxylase, α-KG = α-ketoglutarate, α-KGDH = α-ketoglutarate dehydrogenase, SCS = succinyl-CoA synthetase, SDH = succinate dehydrogenase, LDH = lactate dehydrogenase.

Figure 4.. Monoaminylation of histones.

a) Examples of biogenic amines that TGM2 can use as cofactors. b) TGM2 transfers monoamines to glutamate residues in histones, releasing ammonia. While an enzyme has not yet been identified that can remove histone monoaminylation to restore the unmodified glutamine, TGM2 may be able to replace the first monoamine with a second depending on the relative abundance of the monoamines. TGM2 = tissue transglutaminase 2.

Figure 5.. Spatial control of cellular acetyl-CoA.

ACLY, ACSS2, and PDC use citrate, acetate, and pyruvate, respectively, to generate acetyl-CoA that is available for histone acetylation. Under certain conditions these enzymes translocate to the nucleus where they can provide localized production of the cofactor, potentially contributing to chromatin regulation through histone acetylation pathways. ACLY = ATP citrate lyase, ACSS2 = Acyl-CoA synthetase short-chain family member 2, PDC = pyruvate dehydrogenase complex, HAT = histone acetyltransferase, HDAC = histone deacetylase, TCA cycle = tricarboxylic acid cycle.

Figure 6.. Compartmentalized NAD⁺ synthesis coordinates glucose metabolism and transcription.

In an undifferentiated state (left), NMN is used by the nuclear NMNAT-1 to produce NAD⁺, promoting PARP1-dependent ADP-ribosylation of the transcription factor C/EBPβ to hold the cell in this undifferentiated state. Once proper adipogenic signals are received (top), cytoplasmic NMNAT-2 is induced to produce NAD⁺ for glycolysis, depleting the nuclear NAD⁺ pool and initiating C/EBPβ-mediated adipogenic differentiation (right). PARP1 = poly-ADP-ribose polymerase 1, C/EBPβ = CCAAT-enhancer-binding protein β, NMN = nicotinamide mononucleotide, NMNAT = nicotinamide mononucleotide adenylyltransferase, Pparg = peroxisome proliferator activated receptor gamma.