Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation.

Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.

Metabolic modulation of transcription: The role of one-carbon metabolism.

While it is well known that expression levels of metabolic enzymes regulate the metabolic state of the cell, there is mounting evidence that the converse is also true, that metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. Here we focus on the one-carbon metabolic pathway, which provides the essential building blocks of many classes of biomolecules, including purine nucleotides, thymidylate, serine, and methionine. We review the epigenetic roles of one-carbon metabolic enzymes and their associated metabolites and introduce an interactive computational resource that places enzyme essentiality in the context of metabolic pathway topology. Therefore, we briefly discuss examples of metabolic condensates and higher-order complexes of metabolic enzymes downstream of one-carbon metabolism. We speculate that they may be required to the formation of transcriptional condensates and gene expression control. Finally, we discuss new ways to exploit metabolic pathway compartmentalization to selectively target these enzymes in cancer.

Chromatin as a sensor of metabolic changes during early development.

Cellular metabolism is a complex network of biochemical reactions fueling development with energy and biomass; however, it can also shape the cellular epigenome. Indeed, some intermediates of metabolic reactions exert a non-canonical function by acting as co-factors, substrates or inhibitors of chromatin modifying enzymes. Therefore, fluctuating availability of such molecules has the potential to regulate the epigenetic landscape. Thanks to this functional coupling, chromatin can act as a sensor of metabolic changes and thus impact cell fate. Growing evidence suggest that both metabolic and epigenetic reprogramming are crucial for ensuring a successful embryo development from the zygote until gastrulation. In this review, we provide an overview of the complex relationship between metabolism and epigenetics in regulating the early stages of mammalian embryo development. We report on recent breakthroughs in uncovering the non-canonical functions of metabolism especially when re-localized to the nucleus. In addition, we identify the challenges and outline future perspectives to advance the novel field of epi-metabolomics especially in the context of early development.

Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption.

Epigenetic modifications are responsible for finetuning gene expression profiles to the needs of cells, tissues, and organisms. To rapidly respond to environmental changes, the activity of chromatin modifiers critically depends on the concentration of a handful of metabolites that act as substrates and co-factors. In this way, these enzymes act as metabolic sensors that directly link gene expression to metabolic states. Although metabolites can easily diffuse through the nuclear pore, molecular mechanisms must be in place to regulate epigenetic marker deposition in specific nuclear subdomains or even on single loci. In this review, I explore the possible subcellular sites of metabolite production that influence the epigenome. From the relationship between cytoplasmic metabolism and nuclear metabolite deposition, I converse to the description of a compartmentalized nuclear metabolism. Last, I elaborate on the possibility of metabolic enzymes to operate in phase-separated nuclear microdomains formed by multienzyme and chromatin-bound protein complexes.

Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers.

Nuclear glycogen was first documented in the early 1940s, but its role in cellular physiology remained elusive. In this study, we utilized pure nuclei preparations and stable isotope tracers to define the origin and metabolic fate of nuclear glycogen. Herein, we describe a key function for nuclear glycogen in epigenetic regulation through compartmentalized pyruvate production and histone acetylation. This pathway is altered in human non-small cell lung cancers, as surgical specimens accumulate glycogen in the nucleus. We demonstrate that the decreased abundance of malin, an E3 ubiquitin ligase, impaired nuclear glycogenolysis by preventing the nuclear translocation of glycogen phosphorylase and causing nuclear glycogen accumulation. Re-introduction of malin in lung cancer cells restored nuclear glycogenolysis, increased histone acetylation, and decreased growth of cancer cells transplanted into mice. This study uncovers a previously unknown role for glycogen metabolism in the nucleus and elucidates another mechanism by which cellular metabolites control epigenetic regulation.