Metabolic regulation of chromatin modifications and gene expression

Abstract

Dynamic regulation of gene expression in response to changing local conditions is critical for the survival of all organisms. In metazoans, coherent regulation of gene expression programs underlies the development of functionally distinct cell lineages. The cooperation between transcription factors and the chromatin landscape enables precise control of gene expression in response to cell-intrinsic and cell-extrinsic signals. Many of the chemical modifications that decorate DNA and histones are adducts derived from intermediates of cellular metabolic pathways. In addition, several of the enzymes that can remove these marks use metabolites as part of their enzymatic reaction. These observations have led to the hypothesis that fluctuations in metabolite levels influence the deposition and removal of chromatin modifications. In this review, we consider the emerging evidence that cellular metabolic activity contributes to gene expression and cell fate decisions through metabolite-dependent effects on chromatin organization.

Figure 1.

Paradigms of metabolic regulation of gene expression. (A) Summarized model of the E. coli lac operon as outlined by Jacob and Monod (1961). In low glucose/high lactose conditions, the lac repressor (LacI) binds allolactose and RNA polymerase is able to activate transcription of genes required for lactose metabolism. Conversely, in high glucose/low lactose conditions, LacI is not bound to allolactose and can bind to the operator sequence, repressing the ability of RNA polymerase to transcribe operon genes. CAP, catabolite activator protein. (B) Schematic representation of how sequence-specific DNA binding proteins recruit chromatin modifying enzymes that serve to deposit inhibitory (left) or activating (right) marks. In this model, transcription factors recruit local chromatin modifying enzymes. YFG, your favorite gene; 5mC, 5-methyl-cytosine; K9, histone H3 lysine 9; K27, histone H3 lysine 27; K4, histone H3 lysine 4.

Figure 2.

Metabolic pathways provide substrates for enzymes that modify chromatin. (A) Metabolic pathways implicated in the generation of carbon groups required for methylation (turquoise), acetylation (orange), or demethylation (dark blue) of chromatin. Note that TCA cycle metabolites serve to provide carbon units for both acetylation and demethylation via αKG. THF, tetrahydrofolate; SAH, S-adenosylhomocysteine; MTs, methyltransferases; PDC, pyruvate dehydrogenase complex. Details in the text. (B) Chromatin modification reactions that require intermediary metabolites. Repressed chromatin is shown on the left; open chromatin is shown on the right; and a poised state is indicated in the center. Color coding is as in A, with methyl marks in turquoise and acetylation in orange. 5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are indicated, but their reactions are omitted for clarity. HATs, histone acetyltransferases; JMJD, Jumonji-domain containing histone demethylases; KMTs, histone lysine methyltransferases; YFG, your favorite gene. For simplicity, the flavin-dependent LSD1 family of histone demethylases and the sirtuin family NAD-dependent HDACs are omitted but are discussed in the text.

Figure 3.

Subcellular localization of selected metabolic pathways. A simplified schematic depicting the interplay between mitochondrial, cytoplasmic, and nuclear metabolism. Metabolic enzymes found to localize to the nucleus: methionine adenosyl-transferase (MAT), ATP-citrate lyase (ACL), pyruvate dehydrogenase complex (PDC), and ACSS2. Metabolite transport across the inner mitochondrial membrane requires transporters that are shown in simplified form. Note: complete enzymatic reactions are not depicted; we highlight the metabolites directly relevant to chromatin regulation for simplicity.