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Acetate Supplementation Restores Cognitive Deficits Caused by ARID1A Haploinsufficiency in Excitatory Neurons

ABSTRACT: Mutations in AT-rich interactive domain-containing protein 1A (ARID1A) cause Coffin-Siris syndrome (CSS), a rare genetic disorder that results in mild to severe intellectual disabilities. However, the biological role of ARID1A in the brain remains unclear. In this study, we report that the haploinsufficiency of ARID1A in excitatory neurons causes cognitive impairment and defects in hippocampal synaptic transmission and dendritic morphology in mice. Similarly, human embryonic stem cell-derived excitatory neurons with deleted ARID1A exhibit fewer dendritic branches and spines, and abnormal electrophysiological activity. Importantly, supplementation of acetate, an epigenetic metabolite, can ameliorate the morphological and electrophysiological deficits observed in mice with Arid1a haploinsufficiency, as well as in ARID1A-null human excitatory neurons. Mechanistically, transcriptomic and ChIP-seq analyses demonstrate that acetate supplementation can increase the levels of H3K27 acetylation at the promoters of key regulatory genes associated with neural development and synaptic transmission. Collectively, these findings support the essential roles of ARID1A in the excitatory neurons and cognition and suggest that acetate supplementation could be a potential therapeutic intervention for CSS.

SUBMITTER: Prof. Chang-Mei Liu

PROVIDER: S-SCDT-10_15252-EMMM_202215795 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing ?-ketoglutarate (?KG). ?KG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.

Project description:BackgroundFetal-neonatal iron deficiency causes learning/memory deficits that persist after iron repletion. Simplified hippocampal neuron dendrite structure is a key mechanism underlying these long-term impairments. Early life choline supplementation, with postnatal iron repletion, improves learning/memory performance in formerly iron-deficient (ID) rats.ObjectivesTo understand how choline improves iron deficiency-induced hippocampal dysfunction, we hypothesized that direct choline supplementation of ID hippocampal neurons may restore cellular energy production and dendrite structure.MethodsEmbryonic mouse hippocampal neuron cultures were made ID with 9 μM deferoxamine beginning at 3 d in vitro (DIV). At 11 DIV, iron repletion (i.e., deferoxamine removal) was performed on a subset of ID cultures. These neuron cultures and iron-sufficient (IS) control cultures were treated with 30 μM choline (or vehicle) between 11 and 18 DIV. At 18 DIV, the independent and combined effects of iron and choline treatments (2-factor ANOVA) on neuronal dendrite numbers, lengths, and overall complexity and mitochondrial respiration and glycolysis were analyzed.ResultsCholine treatment of ID neurons (ID + Cho) significantly increased overall dendrite complexity (150, 160, 180, and 210 μm from the soma) compared with untreated ID neurons to a level of complexity that was no longer significantly different from IS neurons. The average and total length of primary dendrites in ID + Cho neurons were significantly increased by ∼15% compared with ID neurons, indicating choline stimulation of dendrite growth. Measures of mitochondrial respiration, glycolysis, and ATP production rates were not significantly altered in ID + Cho neurons compared with ID neurons, remaining significantly reduced compared with IS neurons. Iron repletion significantly improved mitochondrial respiration, ATP production rates, overall dendrite complexity (100-180 μm from the soma), and dendrite and branch lengths compared with untreated ID neurons.ConclusionsBecause choline partially restores dendrite structure in ID neurons without iron repletion, it may have therapeutic potential when iron treatment is not possible or advisable. Choline's mechanism in ID neurons requires further investigation.

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Acetate Supplementation Restores Cognitive Deficits Caused by ARID1A Haploinsufficiency in Excitatory Neurons

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