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Review
. 2020 Jul 29:8:671.
doi: 10.3389/fcell.2020.00671. eCollection 2020.

Insight on Transcriptional Regulation of the Energy Sensing AMPK and Biosynthetic mTOR Pathway Genes

Abitha Sukumaran  1 , Kwangmin Choi  2 , Biplab Dasgupta  1
Affiliations
Review

Insight on Transcriptional Regulation of the Energy Sensing AMPK and Biosynthetic mTOR Pathway Genes

Abitha Sukumaran et al. Front Cell Dev Biol. .

Abstract

The Adenosine Monophosphate-activated Protein Kinase (AMPK) and the Mechanistic Target of Rapamycin (mTOR) are two evolutionarily conserved kinases that together regulate nearly every aspect of cellular and systemic metabolism. These two kinases sense cellular energy and nutrient levels that in turn are determined by environmental nutrient availability. Because AMPK and mTOR are kinases, the large majority of studies remained focused on downstream substrate phosphorylation by these two proteins, and how AMPK and mTOR regulate signaling and metabolism in normal and disease physiology through phosphorylation of their substrates. Compared to the wealth of information known about the signaling and metabolic pathways modulated by these two kinases, much less is known about how the transcription of AMPK and mTOR pathway genes themselves are regulated, and the extent to which AMPK and mTOR regulate gene expression to cause durable changes in phenotype. Acute modification of cellular systems can be achieved through phosphorylation, however, induction of chronic changes requires modulation of gene expression. In this review we will assemble evidence from published studies on transcriptional regulation by AMPK and mTOR and discuss about the putative transcription factors that regulate expression of AMPK and mTOR complex genes.

Keywords: AMPK; mTOR; metabolism; signaling; transcription.

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Figures

FIGURE 1
FIGURE 1
Heatmap-style “occurrence” plots of putative AMPK family TFs. The occurrence plot is an intuitive way to visualize co-regulated genes whose expressions are controlled by the same TF(s). Briefly, we assigned “1” if the binding site(s) of a given TF’s (right) are reported “at least once” (in ENCODE) within a reasonable distance from the transcription start site (TSS) of a gene (bottom). Otherwise, we assigned “0” (i.e., no TFBS within a given range). The result is a matrix filled with 0 (w/o TFBS) and 1 (w/TFBS). The trees on the top and the left sides were generated using the hierarchical clustering based on vectors in rows and columns. AMPK pathway genes and TF-binding peak occurrence are shown in the promoter regions. Each red cell represents a gene with at least one binding sites of a given TF within 2 kb-upstream and 1 kb-downstream from its TSS.
FIGURE 2
FIGURE 2
Heatmap-style “occurrence” plots of putative mTOR family TFs. The occurrence plot is an intuitive way to visualize co-regulated genes whose expressions are controlled by the same TF(s). Briefly, we assigned “1” if the binding site(s) of a given TF’s (right) are reported “at least once” (in ENCODE) within a reasonable distance from the transcription start site (TSS) of a gene (bottom). Otherwise, we assigned “0” (i.e., no TFBS within a given range). The result is a matrix filled with 0 (w/o TFBS) and 1 (w/TFBS). The trees on the top and the left sides were generated using the hierarchical clustering based on vectors in rows and columns. mTOR pathway genes and TF-binding peak occurrence are shown in the promoter regions. Each red cell represents a gene with at least one binding sites of a given TF within 2 kb-upstream and 1 kb-downstream from its TSS.
FIGURE 3
FIGURE 3
Indirect transcriptional control by AMPK through metabolites of intermediary metabolism. (a) Intermediary metabolism of glucose, fatty acids and ketogenic amino acids leads to the formation of acetyl-CoA. By regulating glycolysis and fatty acid oxidation AMPK may determine cellular acetyl-CoA levels. Histone acetyltransferases (HATs) use acetyl-CoA to transfer acetyl group to nucleosomal histones. (b) α ketoglutarate dehydrogenase subunit E2 (α-KGDH) complex binds to lysine acetyltransferase 2A (KAT2A). α-KGDH synthesizes succinyl CoA locally and KAT2A succinylates histone H3 on lysine 79 (H3K79). AMPK regulates TCA cycle thereby may influence this process. (c) NAD generated in the mitochondrial electron transport chain acts as a cofactor for SIRT1 and SIRT6 which deacetylates histone H3K9/14 and H3K9/56, respectively. (d) α-ketoglutarate (α-KG), generated through TCA cycle acts as a cofactor for lysine demethylases (KDM) and ten-eleven translocation (TET) enzymes. TETs oxidize 5-methyl-2′-deoxycytidine in genomic DNA to 5-hydroxymethylcytosine (5hmC), 5-carboxylcytosine (5caC), and 5-formylcytosine (5fC) that is involved in epigenetic regulation. FAD generated in the mitochondrial electron transport chain acts as a cofactor for KDMs. (e) AMPK potentially regulates the hexosamine pathway by providing precursors. UDP-GlcNAc is derived from glycolysis and glutamine, the latter being generated by transamination of α ketoglutarate. O-GlcNAcyltransferase (OGT) transfers GlcNAc residues to various nuclear proteins including TETs and histone 2B (H2B), OCT4 and SOX2 to control transcription.
FIGURE 4
FIGURE 4
Transcriptional regulation by mTORC1. (a) mTORC1 regulates fatty acid synthesis by enabling SREBP1 mediated transcription. Lipin 1 inhibits SREBPs from binding to their target genes. mTORC1 phosphorylates Lipin 1 and prevents its translocation to the nucleus. S6K1 phosphorylation by mTORC1 is required for cleavage and activation of SREBP1c through a yet unknown mechanism. (b) mTORC1 phosphorylates S6K1 and activates tripartite motif-containing protein-24 (TIF24) and promotes its interaction with Pol I. Phosphorylated S6K1 also promotes the interaction of upstream binding factor (UBF) with SL1 regulating rRNA expression. mTORC1 phosphorylates MAF 1 which is a repressor of Pol III thereby controlling the expression of 5srRNA and tRNA. (c) mTORC1 phosphorylates S6K2 which interacts with nuclear receptor corepressor 1 (nCoR1) promoting its translocation to the nucleus thereby inhibiting PPARα. (d) mTORC1 phosphorylates TFEB in the surface of lysosomes promoting its binding to 14-3-3 proteins inhibiting its transport into nucleus. (e) Nuclear mTORC1 interacts with YY1 which in turn modulates the transcriptional activity of PGC1α. (f) mTORC1 phosphorylates STAT5 and promotes SREBP1 transcriptional activity. (g) mTORC1 phosphorylates STAT3 allowing transcription of STAT3 target genes. (h,i) mTORC1 regulates HIF1α and PPARƔ transcription through unknown mechanisms.
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