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.

ACSS2 contributes to transcriptional regulation in Cajal-Retzius cells in a mouse model of Alzheimer’s disease

“…Since inhibiting metabolic-epigenetic interactions by knocking out the nuclear metabolic enzyme ACSS2 exacerbates molecular and behavioral phenotypes observed in the mouse AD-tau model, we considered that stimulating this pathway by supplying the substrate of ACSS2, acetate, might have beneficial effects. Acetate supplementation to primary hippocampal neurons drives genes of learning and memory and promotes cognitive function in a developmental mouse model 42 , and acetate gavage can promote memory in the 5xFAD mouse 43 . To investigate and define mechanisms of acetate supplementation in modulation of gene function for learning and memory in normal mice, first we tested whether exogenous acetate is directly incorporated into hippocampal histone acetylation, using heavy labeled acetate.…”

Clinical outcome and molecular landscape of patients with ARID1A‐loss gastric cancer

“…16 However, due to the presence of haploinsufficiency, ARID1A loss of function could also be a result of copy number deletion. 17,18 This indicated that GC patients with either ARID1A point mutation or copy number deletion might refer to the same entity. Thus, in this study, we defined ARID1A loss as either point mutation or copy number deletion and analyzed the clinicopathologic, genomic, and immunophenotypic correlates of ARID1A-loss GC, which might give us a more comprehensive understanding for the impact of ARID1A alteration on GC and guide precision treatment for these patients.…”

“…In GC, our previous study revealed that somatic ARID1A mutation could predict superior response to fluorouracil‐based adjuvant chemotherapy (ACT) and anti‐PD1 immunotherapy 16 . However, due to the presence of haploinsufficiency, ARID1A loss of function could also be a result of copy number deletion 17,18 . This indicated that GC patients with either ARID1A point mutation or copy number deletion might refer to the same entity.…”

Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability

“…Indeed, our findings in human Fib-iNs would suggest the opposite strategy in the adult CNS, using Arid1a overexpression to increase regeneration. In excitatory human neurons derived from embryonic stem cells, ARID1A knockout results in decreased dendritic length and reduced synaptic markers (74), though only dendritic growth specifically was measured. Taken together, these and other studies have established a role for ARID1A in pioneer axon growth, dendritic complexity, and synaptic density.…”