Acetate supplementation restores cognitive deficits caused by ARID1A haploinsufficiency in excitatory neurons

• Published in: EMBO molecular medicine Vol. 14; no. 12; pp. e15795 - n/a
• Main Authors: Liu, Pei‐Pei, Dai, Shang‐Kun, Mi, Ting‐Wei, Tang, Gang‐Bin, Wang, Zhuo, Wang, Hui, Du, Hong‐Zhen, Tang, Yi, Teng, Zhao‐Qian, Liu, Chang‐Mei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.12.2022; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: acetate; Acetates - pharmacology; Acetates - therapeutic use; Acetic acid; Acetylation; Animal memory; Animals; ARID1A; Behavior; Cognition & reasoning; Cognition - drug effects; Cognitive ability; cognitive deficit; Cytology; Dendritic spines; Disability; DNA-Binding Proteins - genetics; EMBO27; Epigenetics; excitatory neurons; Genetic disorders; Haploinsufficiency; Hippocampus; Humans; Intellectual disabilities; Intellectual Disability - drug therapy; Mice; Mutation; Neurons; Neurons - drug effects; Stem cells; Supplements; SWI/SNF; Synaptic transmission; Synaptogenesis; Transcription Factors - genetics; Transcriptome; Transcriptomics; acetate; cognitive deficit; excitatory neurons; ARID1A; SWI/SNF
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202215795

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. Synopsis Mutations in ARID1A cause Coffin‐Siris syndrome (CSS), a rare genetic disorder with severe neurodevelopmental deficits. This study investigates the genetic basis of the pathophysiological role of ARID1A in CSS and proposes a potential therapeutic intervention. Arid1a haploinsufficiency in mouse excitatory neurons leads to spatial memory defects. ARID1A is required for neuron dendritic and synapse growth in mice and humans. Acetate supplementation rescues the neuronal deficits by increasing H3K27 acetylation levels at the promoters of neuronal genes in both Arid1a haploinsufficient mice and ARID1A KO hESC‐derived neurons. Graphical Abstract Mutations in ARID1A cause Coffin‐Siris syndrome (CSS), a rare genetic disorder with severe neurodevelopmental deficits. This study investigates the genetic basis of the pathophysiological role of ARID1A in CSS and proposes a potential therapeutic intervention.