Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases

Abstract

Cell fate determination requires faithful execution of gene expression programs, which are increasingly recognized to respond to metabolic inputs. In particular, the family of α-ketoglutarate (αKG)-dependent dioxygenases, which include several chromatin-modifying enzymes, are emerging as key mediators of metabolic control of cell fate. αKG-dependent dioxygenases consume the metabolite αKG (also known as 2-oxoglutarate) as an obligate cosubstrate and are inhibited by succinate, fumarate, and 2-hydroxyglutarate. Here, we review the role of these metabolites in the control of dioxygenase activity and cell fate programs. We discuss the biochemical and transcriptional mechanisms enabling these metabolites to control cell fate and review evidence that nutrient availability shapes tissue-specific fate programs via αKG-dependent dioxygenases.

Keywords: 2-hydroxyglutarate; alpha-ketoglutarate; cell fate; chromatin modifications; succinate; αKG-dependent dioxygenases.

Figure 1.. Metabolic Regulation of α-Ketoglutarate-Dependent Dioxygenases.

(A) Schematic of key pathways involved in synthesis and break down of α-ketoglutarate (αKG), 2-hydroxyglutarate (2HG), fumarate, and succinate. Enzymes directly involved in αKG metabolism are shown in blue, those involved in 2HG, fumarate, and succinate metabolism are shown in red. (B) Generalized schematic of αKG-dependent dioxygenase (also known as 2-oxoglutarate dependent dioxygenase or OGDD) action on your favorite target (YFT). Dioxygenases catalyze net demethylation or hydroxylation reactions using αKG and molecular oxygen as cosubstrates and producing succinate as a by-product. Vitamin C, oxygen, and αKG can promote dioxygenase activity, whereas succinate, fumarate, and 2HG have been shown to suppress their activity. (C) Enzymatic assays provide potential insights into metabolic regulation of dioxygenase catalytic activity. In this example, dioxygenase B is expected to be sensitive to physiological fluctuations in αKG concentrations, whereas dioxygenase A will be less sensitive. However, it remains unclear what true physiological αKG concentrations are, given that dioxygenases may be sensitive to compartmentalized metabolite pools. Abbreviations: FH, Fumarate hydratase; IDH, isocitrate dehydrogenase; mtIDH, IDH mutations; SDH, succinate dehydrogenase; TCA, tricarboxylic acid.

Figure 2.. Mechanisms of Metabolic Control of Cell Fate.

(A) α-Ketoglutarate (αKG)-dependent dioxygenases can directly impact expression of key transcription factors (KTFs) by regulating either mRNA methylation via FTO and ALKBH5 or protein hydroxylation by prolyl hydroxylases (PHDs), each of which trigger target degradation. (B) Metabolites can regulate transcription factor (TF) function by influencing function of transcriptional coactivators, a subset of which are αKG-dependent dioxygenases. Transcription factors recruit coactivators such as ten-eleven translocation (TET) DNA cytosine oxidizing enzymes and Jumonji C-domain lysine demethylases (KDMs) to target loci in order to locally remodel chromatin. (C) Metabolites can affect enhancer function and long-range chromatin interactions by controlling CCCTC-binding factor (CTCF) binding to DNA, which is suppressed by DNA methylation. αKG enforces topologically associated domains (TAD) architecture in cells by facilitating CTCF binding, whereas 2-hydroxyglutarate (2HG), succinate, and fumarate disrupt TAD architecture. An example scenario illustrates how, in the presence of CTCF, a cell type-specific active enhancer drives expression of your favorite gene-A (YFG-A), whereas YFG-B is suppressed. Upon loss of CTCF binding, however, TAD boundaries are disrupted and the active enhancer drives expression of YFG-B.

Figure 3.. Niche Regulation of α-Ketoglutarate (αKG)-Dependent Dioxygenases.

Summary of potential regulators of αKG-dependent dioxygenase activity within the stem cell niche. αKG is produced from glutamine-derived glutamate via transamination reactions, which can be suppressed or reversed by extracellular amino acids such as valine and serine. Hypoxia directly antagonizes dioxygenase activity and facilitates production of 2-hydroxyglutarate (2HG) from αKG. The role of niche cells in regulation of αKG-dependent dioxygenase activity has yet to be explored. Niche cells may add another layer of metabolic regulation of dioxygenase function, as many stem cells reside in proximity to the vasculature and stromal cells may provide nutrients to stem cells and/or compete with stem cells for nutrients within the niche.