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Project description:Diabetes mellitus in early pregnancy is a non–genetic maternal risk factor for neural tube defects, which are associated with dysregulated gene expression and disruption of cellular behaviors. However, the key molecules linking high glucose metabolism to gene dysregulation remain unclear. Here, we report elevation of ATP citrate lyase (ACL), a metabolic enzyme of the glucose–related tricarboxylic acid cycle in brains of DM–induced mouse embryos with neural tube defects. Consistent with high glucose exposure, manipulation of ACL expression controlled the levels of acetyl-CoA and subsequent lysine 27 acetylation of histone H3 (H3K27ac). Inhibition of ACL activity significantly ameliorated diabetes mellitus–induced exencephaly in mouse embryos. Combinational analysis of H3K27ac ChIP-seq and RNA-seq data revealed a genome–wide synergistic dysregulation of 566 genes, among which the most highly upregulated gene was Txnip, which encodes a thioredoxin–interacting protein. Manipulation of ACL expression disrupted the levels of TXNIP protein, subsequent phosphorylation of apoptosis signal–regulating kinase 1 (ASK1) and neuroepithelial apoptosis. Such pathogenic pathway involving high glucose–induced ACL–H3K27ac, increased–TXNIP upregulation and excessive apoptosis was validated in human embryonic brain tissue affected by neural tube defects. Our study uncovers an intermediary role of ACL in linking high glucose metabolism to epigenetic alterations and neural tube defect formation.
2023-08-31 | GSE239962 | GEO
Project description:Diabetes mellitus in early pregnancy is a non–genetic maternal risk factor for neural tube defects, which are associated with dysregulated gene expression and disruption of cellular behaviors. However, the key molecules linking high glucose metabolism to gene dysregulation remain unclear. Here, we report elevation of ATP citrate lyase (ACL), a metabolic enzyme of the glucose–related tricarboxylic acid cycle in brains of DM–induced mouse embryos with neural tube defects. Consistent with high glucose exposure, manipulation of ACL expression controlled the levels of acetyl-CoA and subsequent lysine 27 acetylation of histone H3 (H3K27ac). Inhibition of ACL activity significantly ameliorated diabetes mellitus–induced exencephaly in mouse embryos. Combinational analysis of H3K27ac ChIP-seq and RNA-seq data revealed a genome–wide synergistic dysregulation of 566 genes, among which the most highly upregulated gene was Txnip, which encodes a thioredoxin–interacting protein. Manipulation of ACL expression disrupted the levels of TXNIP protein, subsequent phosphorylation of apoptosis signal–regulating kinase 1 (ASK1) and neuroepithelial apoptosis. Such pathogenic pathway involving high glucose–induced ACL–H3K27ac, increased–TXNIP upregulation and excessive apoptosis was validated in human embryonic brain tissue affected by neural tube defects. Our study uncovers an intermediary role of ACL in linking high glucose metabolism to epigenetic alterations and neural tube defect formation.
2023-08-31 | GSE239961 | GEO
Project description:Overactivation of ATP citrate lyase-H3K27 acetylation axis leads to maternal diabetes induced neural tube defect.
| PRJNA1001828 | ENA
Project description:Overactivation of ATP citrate lyase-H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [ChIP-seq]
| PRJNA1001836 | ENA
Project description:Overactivation of ATP citrate lyase–H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [RNA-seq]
| PRJNA1001834 | ENA
Project description:Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure only to low concentrations of extracellular acetate. We have shown that histone acetylation in mammalian cells is dependent on adenosine triphosphate (ATP)-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.
| S-EPMC2746744 | biostudies-literature
Project description:Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose.
| S-EPMC4180208 | biostudies-literature
Project description:The modulation of dynamic histone acetylation states is key for organizing chromatin structure and modulating gene expression and is regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. The mammalian SIRT6 protein, a member of the Class III HDAC Sirtuin family of NAD+-dependent enzymes, plays pivotal roles in aging, metabolism, and cancer biology. Through its site-specific histone deacetylation activity, SIRT6 promotes chromatin silencing and transcriptional regulation of aging-associated, metabolic, and tumor suppressive gene expression programs. ATP citrate lyase (ACLY) is a nucleo-cytoplasmic enzyme that produces acetyl coenzyme A (acetyl-CoA), which is the required acetyl donor for lysine acetylation by HATs. In addition to playing a central role in generating cytosolic acetyl-CoA for de novo lipogenesis, a growing body of work indicates that ACLY also functions in the nucleus where it contributes to the nutrient-sensitive regulation of nuclear acetyl-CoA availability for histone acetylation in cancer cells. In this study, we have identified a novel function of SIRT6 in controlling nuclear levels of ACLY and ACLY-dependent tumor suppressive gene regulation. The inactivation of SIRT6 in cancer cells leads to the accumulation of nuclear ACLY protein and increases nuclear acetyl-CoA pools, which in turn drive locus-specific histone acetylation and the expression of cancer cell adhesion and migration genes that promote tumor invasiveness. Our findings uncover a novel mechanism of SIRT6 in suppressing invasive cancer cell phenotypes and identify acetyl-CoA responsive cell migration and adhesion genes as downstream targets of SIRT6.
| S-EPMC8466468 | biostudies-literature
Project description:Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor (LXR) activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst presenting increased phagocytosis of apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.
2020-02-18 | GSE126690 | GEO
Project description:TLR activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades within the first hours after stimulation. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remain unknown. Here we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Macrophages increase glucose metabolism and adopt fluxes through the TCA cycle to foster Citrate synthesis. We concomitantly observe activation of ATP-Citrate Lyase (Acly), resulting in augmented acetyl-CoA synthesis and histone acetylation. To investigate which genes and genes classes require ATP-citrate lyase activity for induction we stimulated bone marrow derived macrophages with LPS after ATP-citrate lyase inhibition.
2019-12-16 | GSE129497 | GEO