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Review
, 41 (4), 264-270

Cooperative Instruction of Signaling and Metabolic Pathways on the Epigenetic Landscape

Affiliations
Review

Cooperative Instruction of Signaling and Metabolic Pathways on the Epigenetic Landscape

Jung-Ae Kim. Mol Cells.

Abstract

Cells cope with diverse intrinsic and extrinsic stimuli in order to make adaptations for survival. The epigenetic landscape plays a crucial role in cellular adaptation, as it integrates the information generated from stimuli. Signaling pathways induced by stimuli communicate with chromatin to change the epigenetic landscape through regulation of epigenetic modifiers. Metabolic dynamics altered by these stimuli also affect the activity of epigenetic modifiers. Here, I review the current understanding of epigenetic regulation via signaling and metabolic pathways. In addition, I will discuss possible ways to achieve specificity of epigenetic modifications through the cooperation of stimuli-induced signal transduction and metabolic reprogramming.

Keywords: cancer; differentiation; epigenetics; metabolism; signaling.

Figures

Fig. 1
Fig. 1. Cooperation of AKT signaling pathway and the accompanied upregulation of acetyl-CoA metabolism to promote histone acetylation
Growth factor-induced AKT signaling pathway upregulates acetyl-CoA production and phosphorylates histone modifying enzymes such as p300 and EZH2 to enhance histone acetylation on chromatin. The enzymes involved in the pathways are in bold. P in green dots denotes for phosphorylation-mediated regulation. Ac and Me refer to acetylation and methylation, respectively. GLUT1; glucose transporter 1, HK1; hexose kinase 1, PFK1/2; phosphofructokinase 1/2, RTKs; receptor tyrosine kinases, PI3K; phosphoinositide 3-kinae, ACL; ATP-citrate lyase, EZH2; enhancer of zeste homolog 2.
Fig. 2
Fig. 2. Energy stress induced AMPK signaling to promote NAD+-dependent SIRT1 activity
Upon energy stress-stimuli, the AMPK signaling pathway is upregulated, resulting in the increase of intracellular NAD+ level. At the same time, histone deacetylase SIRT1 and/or transcription factors such as PGC-1α are phosphorylated in AMPK-dependent manner. The enzymes involved in the pathways are in bold. P in green dots denotes for phosphorylation-mediated regulation. De-Ac in blue circles indicates deacetylation-mediated regulation. AMPK; AMP-activated kinase, NAMPT; nicotinamide phosphoribosyltransferase, SIRT1; sirtuin 1, PGC-1α; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, AICAR; 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside.
Fig. 3
Fig. 3. Cooperation of SAM metabolism and cell signaling to alter DNA/histone methylation
DNA/histone methylation is tightly linked with one-carbon metabolism. The oncogenic JAK2 signaling pathway regulates arginine methyltransferase PRMT5 activity and subsequently modulates methylation of histones and non-histone proteins, including transcription factors, NF-κB, p53 and E2F-1. The enzymes involved in the pathways are in bold. Metabolism pathways are marked in italic. P in green dots denotes for phosphorylation-mediated regulation. TDH; threonine dehydrogenase, MTAP; methylthioadenosine phosphorylase, PRMT5; protein arginine N-methyltransferase 5, JAK2; Janus kinase 2, DNMT1/3; DNA methyltransferase 1/3, LKB1; liver kinase B1, mTOR; mechanistic target of rapamycin, SAM; S-adenosylmethionine, SAH; S-adenosylhomocysteine, Hcy; homocysteine, MTA; methylthioadenosine.
Fig. 4
Fig. 4. Stimuli-responsive cellular adaptations through specific epigenetic regulation
Cellular stimuli induce signaling cascades and metabolic reprogramming, leading to the modification of epigenetic regulators and transcription factors at multiple levels, such as posttranslational modifications or the availability of metabolites. Subsequent epigenetic changes targeted by the epigenetic regulators, along with interacting transcription factors, mediate cellular adaptations to the given stimuli by modulating gene expressions.

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