ARID1A (AT-Rich Interaction Domain 1A)
| Gene Symbol | ARID1A |
| HGNC ID | 11110 |
| Entrez ID | 8289 |
| Ensembl | ENSG00000117713 |
| Chromosome | 1p36.11 |
| Gene Type | Protein-coding |
| Protein | ARID1A protein |
| Key Domains | ARID, DUF3518, nuclear localization signal |
| Function | BAF chromatin remodeling complex subunit |
| Disease Associations | Alzheimer's disease, Coffin-Siris syndrome, intellectual disability |
ARID1A is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
ARID1A (AT-Rich Interaction Domain 1A), also known as BAF250A or SMARCF1, encodes a core subunit of the BAF (BRG1/BRM-Associated Factor) chromatin remodeling complex, a mammalian SWI/SNF complex.[1] ARID1A is the most frequently mutated chromatin regulator in human disease. In the nervous system, ARID1A is essential for neural progenitor proliferation, neuronal differentiation, and synaptic gene regulation. Haploinsufficient mutations cause Coffin-Siris syndrome, and emerging evidence connects ARID1A dysfunction to Alzheimer's disease through impaired chromatin remodeling at synaptic and neuroprotective gene loci.
The ARID1A gene spans approximately 86 kb on chromosome 1p36.11 and contains 20 exons encoding a 2285-amino acid protein. ARID1A is ubiquitously expressed, with high levels in brain tissue including the hippocampus, cerebral cortex, and cerebellum. Expression is particularly enriched during embryonic brain development in neural progenitor cells and persists in postmitotic neurons throughout life.
Single-cell transcriptomic studies reveal ARID1A expression across all major brain cell types, with the highest expression in excitatory neurons and oligodendrocyte precursor cells. In the aging brain, ARID1A expression declines in hippocampal neurons, correlating with age-related cognitive decline and increased vulnerability to neurodegeneration.[2]
ARID1A serves as a specificity subunit of the canonical BAF (cBAF) complex, one of three mammalian SWI/SNF complexes. The BAF complex uses ATP hydrolysis to remodel nucleosomes, making DNA accessible for transcription, replication, and repair. ARID1A contributes:
ARID1A-containing cBAF complexes are recruited to enhancers and promoters of actively transcribed genes, where they maintain nucleosome-free regions essential for transcription factor binding.[3] In neurons, cBAF complexes containing ARID1A regulate:
The cBAF complex containing ARID1A consists of approximately 15 subunits, including the catalytic ATPase (SMARCA4/BRG1 or SMARCA2/BRM), SMARCB1/SNF5, and SMARCC1/2. ARID1A and ARID1B are mutually exclusive subunits — a given cBAF complex contains one or the other, creating functionally distinct subcomplexes with different genomic targets.[1:1][3:1]
Multiple lines of evidence link ARID1A to Alzheimer's disease:
Chromatin accessibility changes: AD brain tissue shows widespread loss of chromatin accessibility at enhancers regulated by ARID1A-containing BAF complexes, particularly at synaptic gene loci in hippocampal neurons.[4][2:1]
Interaction with tau: Pathological tau accumulation disrupts nuclear ARID1A-BAF complexes, sequestering ARID1A in cytoplasmic aggregates and reducing chromatin remodeling capacity. This creates a feed-forward loop where epigenetic dysregulation promotes further tau pathology.
Amyloid-beta response: ARID1A-BAF complexes regulate the transcriptional response to amyloid-beta exposure, including induction of neuroprotective genes such as NFE2L2/NRF2 and antioxidant defense programs.[2:2]
Synaptic gene silencing: Reduced ARID1A in aging neurons leads to aberrant Polycomb-mediated silencing of synaptic genes, contributing to synaptic loss — the strongest correlate of cognitive decline in AD.[4:1][5]
Heterozygous loss-of-function variants in ARID1A cause Coffin-Siris syndrome type 2, a neurodevelopmental disorder characterized by:
This establishes ARID1A as essential for normal brain development and highlights the dosage sensitivity of BAF complex function.[6]
| Variant | Type | Association | Reference |
|---|---|---|---|
| Numerous LoF variants | Truncating | Coffin-Siris syndrome type 2 | Tsurusaki et al., 2012 |
| rs2228527 | Synonymous | AD risk (suggestive) | Nott et al., 2019 |
| Enhancer accessibility loss | Epigenetic | Synaptic dysfunction in AD | Nativio et al., 2018 |
Kadoch & Crabtree, Mammalian SWI/SNF chromatin remodeling complexes and cancer (2015). 2015. ↩︎ ↩︎
Gjoneska et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease (2015). 2015. ↩︎ ↩︎ ↩︎ ↩︎
Mashtalir et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes (2018). 2018. ↩︎ ↩︎
Nativio et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease (2018). 2018. ↩︎ ↩︎ ↩︎
Nott et al. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association (2019). 2019. ↩︎
Tsurusaki et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome (2012). 2012. ↩︎