State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
EMBO Mol Med. 2022 Dec 7;14(12):e15795. doi: 10.15252/emmm.202215795. Epub 2022 Nov 17.
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.
ARID1A 基因中的突变会导致 Coffin-Siris 综合征（CSS），这是一种罕见的遗传疾病，会导致轻度至重度的智力障碍。然而，ARID1A 在大脑中的生物学作用仍不清楚。在这项研究中，我们报告称，兴奋性神经元中的 ARID1A 杂合不足会导致小鼠认知障碍以及海马突触传递和树突形态缺陷。同样，缺失 ARID1A 的人类胚胎干细胞衍生兴奋性神经元的树突分支和棘突较少，并且表现出异常的电生理活动。重要的是，添加组蛋白乙酰转移酶的代谢产物乙酰辅酶 A 可以改善 Arid1a 杂合不足的小鼠以及 ARID1A 缺失的人类兴奋性神经元中观察到的形态和电生理缺陷。从机制上讲，转录组和 ChIP-seq 分析表明，乙酰辅酶 A 补充可以增加与神经发育和突触传递相关的关键调节基因启动子处的 H3K27 乙酰化水平。总之，这些发现支持了 ARID1A 在兴奋性神经元和认知中的重要作用，并表明补充乙酰辅酶 A 可能是治疗 CSS 的一种潜在治疗方法。
