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.
|
Authors | Pei-Pei Liu, Shang-Kun Dai, Ting-Wei Mi, Gang-Bin Tang, Zhuo Wang, Hui Wang, Hong-Zhen Du, Yi Tang, Zhao-Qian Teng, Chang-Mei Liu |
Journal | EMBO molecular medicine
(EMBO Mol Med)
Vol. 14
Issue 12
Pg. e15795
(12 07 2022)
ISSN: 1757-4684 [Electronic] England |
PMID | 36385502
(Publication Type: Journal Article)
|
Copyright | ©2022 The Authors. Published under the terms of the CC BY 4.0 license. |
Chemical References |
- Acetates
- ARID1A protein, human
- Arid1a protein, mouse
- DNA-Binding Proteins
- Transcription Factors
|
Topics |
- Animals
- Humans
- Mice
- Acetates
(pharmacology, therapeutic use)
- Cognition
(drug effects)
- DNA-Binding Proteins
(genetics)
- Transcription Factors
(genetics)
- Transcriptome
- Haploinsufficiency
- Neurons
(drug effects)
- Intellectual Disability
(drug therapy)
|