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Regulation of chromatin and gene expression by metabolic enzymes and metabolites

Abstract

Metabolism and gene expression, which are two fundamental biological processes that are essential to all living organisms, reciprocally regulate each other to maintain homeostasis and regulate cell growth, survival and differentiation. Metabolism feeds into the regulation of gene expression via metabolic enzymes and metabolites, which can modulate chromatin directly or indirectly — through regulation of the activity of chromatin trans-acting proteins, including histone-modifying enzymes, chromatin-remodelling complexes and transcription regulators. Deregulation of these metabolic activities has been implicated in human diseases, prominently including cancer.

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Fig. 1: Chromatin modulation by metabolites.
Fig. 2: Regulation of chromatin methylation by metabolic enzymes and metabolites and their roles in DNA repair.
Fig. 3: Core metabolic functions of metabolic enzymes that also function in epigenetic modifications.
Fig. 4: The roles of nuclear PKM2 in gene expression.
Fig. 5: Acetylation of histones regulated by metabolic enzymes and metabolites.
Fig. 6: Association of metabolites and metabolic enzymes with cancer development.

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Acknowledgements

This work was supported by National Institute of Neurological Disorders and Stroke grant R01 NS089754 (to Z.L.), NCI grants 2R01 CA109035 and R01CA204996 (to Z.L.) and the US National Institutes of Health (NIH) National Cancer Institute (NCI) under award number P30CA016672, 2P50 CA127001 (Brain Cancer SPORE). Z.L. is a Ruby E. Rutherford Distinguished Professor.

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Nature Reviews Molecular Cell Biology thanks Y. Zhao and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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X.L., G.E., S.L.B. and Z.L. wrote the article. All authors researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript.

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Correspondence to Shelley L. Berger or Zhimin Lu.

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Glossary

Cofactors

Non-protein chemical compounds or metallic ions that are required for the activity of an enzyme.

β-Oxidation

The catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA.

Ketone bodies

Any of three related compounds (acetone, acetoacetic acid and β-hydroxybutyric acid) produced during the metabolism of fats.

Streptozotocin

A naturally occurring alkylating anti-neoplastic agent that is particularly toxic to the insulin-producing β-cells of the pancreas in mammals.

Homeotic genes

A group of genes that regulates the development of anatomical structures in various organisms.

Linker histone

Member of a family of histones that bind to the nucleosomal core particle around the DNA entry and exit sites and serve as key components of chromatin. Also known as H1 histone.

β-Catenin

A protein that regulates cell–cell adhesion and gene transcription by translocating to the nucleus and associating with T cell factor (TCF) and lymphoid enhancer factor (LEF) transcription factors; it is encoded by the CTNNB1 gene.

Warburg effect

The elevated glucose uptake and lactate production observed in many cancer cell lines regardless of oxygen availability.

Aryl hydrocarbon receptor

(AhR). A ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic (aryl) hydrocarbons.

Pentose phosphate pathway

A glycolysis-parallel metabolic pathway that generates NADPH, pentoses and ribose 5-phosphate for nucleotide synthesis.

DNA-dependent protein kinase

(DNA-PK). A nuclear serine/threonine-protein kinase that is activated upon DNA damage.

Histone H2A.Z

An evolutionarily conserved histone variant involved in transcription regulation and genome stability.

Nonhomologous end joining

(NHEJ). A pathway that repairs double-strand DNA breaks by direct ligation without the need for a homologous template.

Hereditary leiomyomatosis

An autosomal dominant condition in which susceptible individuals are at risk of the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer.

Gluconeogenesis

A metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol and glucogenic amino acids.

von Hippel–Lindau

An inherited disorder characterized by the formation of tumours and fluid-filled sacs (cysts) in many different parts of the body.

Retinitis pigmentosa

A genetic disorder of the eyes that causes loss of vision.

Ecdysone

A steroid hormone secreted by the prothoracic gland that, in its active form, stimulates metamorphosis and regulates moulting in insects.

NuRD complex

The nucleosome remodelling and deacetylase complex.

SWI/SNF complex

An evolutionarily conserved multisubunit chromatin-remodelling complex that uses the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin.

Haem

The component of haemoglobin (and other haemoproteins) responsible for binding oxygen.

Haematocrit

The ratio of the volume of red blood cells to the total volume of blood.

Homologous recombination

(HR). A type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA.

Ataxia-telangiectasia mutated (ATM) kinase

A serine/threonine-protein kinase that is recruited and activated by DNA double-strand breaks.

TP53-binding protein

(53BP1). A protein involved in DNA repair, which is encoded by the TP53BP1 gene.

Breast cancer type 1 susceptibility protein

(BRCA1). A tumour suppressor protein involved in DNA repair.

Retinoblastoma protein

A tumour suppressor protein that inhibits cell cycle progression and is dysfunctional in several major cancers.

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Li, X., Egervari, G., Wang, Y. et al. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat Rev Mol Cell Biol 19, 563–578 (2018). https://doi.org/10.1038/s41580-018-0029-7

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