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Overactivation of ATP citrate lyase-H3K27 acetylation axis leads to maternal diabetes induced neural tube defect.

ABSTRACT: Overactivation of ATP citrate lyase-H3K27 acetylation axis leads to maternal diabetes induced neural tube defect.

PROVIDER: PRJNA1001828 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25502345_1.fastq.gz	Fastqsanger.gz
	SRR25502345_2.fastq.gz	Fastqsanger.gz
	SRR25502346_1.fastq.gz	Fastqsanger.gz
	SRR25502346_2.fastq.gz	Fastqsanger.gz
	SRR25502347_1.fastq.gz	Fastqsanger.gz

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Overactivation of ATP citrate lyase-H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [ChIP-seq]

Project description:Overactivation of ATP citrate lyase-H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [ChIP-seq]

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Overactivation of ATP citrate lyase–H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [RNA-seq]

Project description:Overactivation of ATP citrate lyase–H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [RNA-seq]

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Overactivation of ATP citrate lyase-H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [ChIP-seq]

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.

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Overactivation of ATP citrate lyase–H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [RNA-seq]

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Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase

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.

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Selective autophagic degradation of ATP citrate lyase maintains citrate homeostasis and promotes oocyte maturation

Project description:Autophagy is a cellular and energy homeostatic mechanism that contributes to maintain the number of primordial follicles, germ cell survival, and anti-ovarian aging. However, it remains unknown whether autophagy in granulosa cells affects the oocyte maturation. Here, we show a clear tendency of reduced autophagy level in human granulosa cell from women of advanced maternal age, implying a potential negative correlation between autophagy level and oocyte quality. We therefore established a co-culture system and show that either pharmacological inhibition or genetic ablation of autophagy in granulosa cells negatively affect the oocyte quality and fertilization ability. Moreover, our metabolomics analysis indicates that the adverse impact of autophagy impairment on oocyte quality is mediated by downregulated citrate levels, while exogenous supplementation of citrate can significantly restore the oocyte maturation. In molecular level, we found ATP citrate lyase (Acly), which is a crucial enzyme catalyzing the cleavage of citrate, was preferentially associated with K63-linked ubiquitin chains and recognized by the autophagy receptor protein SQSTM1/p62 for the selective autophagic degradation. In human follicles, autophagy levels in granulosa cells was downregulated with maternal aging, accompanied by decreased citrate in the follicular fluid, implying a potential correlation between citrate metabolism and oocyte quality. We also show that elevated citrate levels in porcine follicular fluid promote oocyte maturation. Collectively, our data reveal that autophagy in granulosa cells is a beneficial mechanism to maintain a certain degree of citrate by selectively targeting Acly during oocyte maturation.

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Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

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