ARID2 (AT-Rich Interaction Domain 2)
<div class="infobox infobox-gene">
<h3>ARID2</h3>
<table> [@mashtalir2018]
<tr><td><strong>Full Name</strong></td><td>AT-Rich Interaction Domain 2</td></tr> [@kadoch2015]
<tr><td><strong>Gene Symbol</strong></td><td>ARID2</td></tr> [@hodges2018]
<tr><td><strong>Aliases</strong></td><td>BAF200, p200</td></tr> [@santen2013]
<tr><td><strong>Chromosomal Location</strong></td><td>12q12</td></tr> [@pan2021]
<tr><td><strong>NCBI Gene ID</strong></td><td>[196528](https://www.ncbi.nlm.nih.gov/gene/196528)</td></tr> [@xu2020]
<tr><td><strong>OMIM</strong></td><td>[609539](https://omim.org/entry/609539)</td></tr> [@mao2022]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000189079](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000189079)</td></tr> [@tsurusaki2012]
<tr><td><strong>UniProt</strong></td><td>[Q68CP9](https://www.uniprot.org/uniprot/Q68CP9)</td></tr>
<tr><td><strong>Protein</strong></td><td>AT-rich interactive domain-containing protein 2</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), Coffin-Siris syndrome, intellectual disability, autism spectrum disorder</td></tr>
</table>
</div>
Overview
PBRM1 is a human gene. Variants in PBRM1 have been implicated in Neurodevelopmental Disorders, Alzheimer's Disease, [Parkinson's Disease](/diseases/parkinsons-disease). This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Gene Function
ARID2 encodes the BAF200 subunit of the Polybromo-associated BAF (PBAF) chromatin remodeling complex, a variant of the mammalian SWI/SNF complex. ARID2/BAF200 is a defining subunit that distinguishes PBAF from canonical BAF (cBAF) and non-canonical BAF (ncBAF) complexes. ARID2 contains an AT-rich interaction domain (ARID) that binds AT-rich DNA sequences, along with RFX-type winged-helix domains and a C2H2 zinc finger, enabling sequence-specific chromatin targeting.
The PBAF complex uses ATP hydrolysis to remodel nucleosomes, sliding, ejecting, or restructuring histone octamers to regulate transcriptional access. ARID2 plays several critical roles in this process:
- Chromatin targeting: The ARID domain of ARID2 recognizes AT-rich DNA sequences prevalent in gene regulatory regions, directing PBAF to specific genomic loci including neural gene enhancers and promoters
- Complex assembly: ARID2 serves as a scaffolding subunit that stabilizes PBAF-specific components including [PBRM1](/genes/pbrm1) (polybromo-1/BAF180), [BRD7](/genes/brd7), and PHF10/BAF45a
- Enhancer regulation: PBAF is preferentially recruited to super-enhancers and poised enhancers marked by H3K4me1, where it facilitates enhancer activation during neural differentiation
- Interferon signaling: ARID2 is required for interferon-stimulated gene (ISG) expression, linking chromatin remodeling to innate immune responses in [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/entities/astrocytes)
- DNA damage response: PBAF is rapidly recruited to DNA double-strand breaks, where it promotes non-homologous end joining (NHEJ) repair by facilitating access of repair machinery to damaged chromatin
Neural Expression and Brain Distribution
ARID2 is broadly expressed throughout the central nervous system, with particularly high levels in:
- Cerebral [cortex](/brain-regions/cortex): Strong expression in pyramidal [neurons](/entities/neurons) across cortical layers, especially in prefrontal and temporal regions critical for cognition
- [Hippocampus](/brain-regions/hippocampus): High expression in CA1-CA3 pyramidal neurons and dentate gyrus granule cells, consistent with roles in learning and memory
- Cerebellum: Purkinje cells show robust ARID2 expression, reflecting requirements for cerebellar chromatin regulation
- Developing brain: Peak expression during embryonic neurogenesis (E12-E18 in mouse), with maintained but reduced adult levels
Single-cell RNA sequencing data show ARID2 expression across all major brain cell types, with highest levels in neurons and oligodendrocyte precursor cells (OPCs).
Disease Associations
Neurodevelopmental Disorders
Heterozygous loss-of-function mutations in ARID2 cause
Coffin-Siris syndrome type 6 (CSS6), characterized by intellectual disability, speech delay, coarse facial features, and hypoplastic fifth fingernails. CSS6 phenotypes overlap with those caused by mutations in other SWI/SNF subunits including [ARID1A](/genes/arid1a), [ARID1B](/genes/arid1b), [SMARCA2](/genes/smarca2), [SMARCA4](/genes/smarca4), and [SMARCB1](/genes/smarcb1), establishing SWI/SNF dysfunction as a convergent mechanism in intellectual disability.
Alzheimer's Disease
ARID2 has emerging connections to [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis through several mechanisms:
- Neuroinflammatory gene regulation: PBAF-dependent chromatin remodeling is required for microglial activation and expression of pro-inflammatory cytokines including [IL-1β](/genes/il1b), [TNF-α](/genes/tnf), and [IL-6](/genes/il6). ARID2 dysfunction may contribute to aberrant neuroinflammatory responses in AD
- [Tau](/proteins/tau) pathology: SWI/SNF complexes regulate expression of [MAPT](/genes/mapt) and tau kinases; disrupted PBAF function alters tau phosphorylation cascades
- Epigenetic drift: Age-related decline in ARID2 expression correlates with progressive loss of chromatin accessibility at neuroprotective gene loci, potentially accelerating neurodegeneration
Parkinson's Disease
- Alpha-synuclein toxicity: PBAF chromatin remodeling protects against [alpha-synuclein](/proteins/alpha-synuclein)-mediated transcriptional dysregulation; ARID2 loss sensitizes dopaminergic neurons to synuclein aggregation
- Mitochondrial gene regulation: PBAF regulates nuclear-encoded mitochondrial genes including [PINK1](/genes/pink1) and [PRKN](/genes/prkn); ARID2 dysfunction may impair mitophagy pathways
Cancer
ARID2 is a frequently mutated tumor suppressor in hepatocellular carcinoma, melanoma, and non-small cell lung cancer. Somatic ARID2 mutations are found in ~7% of hepatocellular carcinomas, making it one of the most commonly mutated chromatin regulators in cancer.
Common Variants
| Variant | Type | Population Frequency | Clinical Significance |
|---------|------|---------------------|----------------------|
| p.Gln1334* | Nonsense | Rare | Coffin-Siris syndrome |
| p.Arg1068Cys | Missense | Rare | Likely pathogenic (NDD) |
| rs17208659 | Intronic | 0.08 (global) | AD risk modifier (suggestive) |
| p.Leu735fs | Frameshift | Rare | Coffin-Siris syndrome |
Therapeutic Implications
- PBAF-targeted therapies: Small molecules that selectively inhibit PBAF (sparing cBAF and ncBAF) are under development for ARID2-mutant cancers; understanding neural effects is critical for CNS safety assessment
- Epigenetic rescue: [HDAC](/entities/hdac-enzymes) inhibitors may partially compensate for PBAF-mediated chromatin accessibility deficits, restoring expression of neuroprotective genes in ARID2-haploinsufficient neurons
- Anti-inflammatory strategies: Modulating ARID2-dependent interferon responses in microglia could reduce neuroinflammation in AD and PD without complete immune suppression
- Gene therapy: AAV-mediated ARID2 supplementation is theoretically feasible but challenged by the large transcript size (~5.5 kb coding sequence)
See Also
- [ARID1A](/genes/arid1a) — cBAF subunit, Coffin-Siris syndrome
- [ARID1B](/genes/arid1b) — cBAF subunit, Coffin-Siris syndrome
- [SMARCA2](/genes/smarca2) — BRM ATPase, Nicolaides-Baraitser syndrome
- [SMARCA4](/genes/smarca4) — BRG1 ATPase, Coffin-Siris syndrome
- [SMARCB1](/genes/smarcb1) — SNF5/INI1, schwannomatosis
- [BRD4](/genes/brd4) — BET bromodomain, super-enhancer regulation
- [NSD1](/genes/nsd1) — H3K36 methyltransferase, Sotos syndrome
External Links
- [NCBI Gene: ARID2](https://www.ncbi.nlm.nih.gov/gene/196528)
- [GeneCards: ARID2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ARID2)
- [OMIM: 609539](https://omim.org/entry/609539)
- [UniProt: Q68CP9](https://www.uniprot.org/uniprot/Q68CP9)
- [Allen Brain Atlas: ARID2](https://portal.brain-map.org/)
References
[Yan et al., BAF250B/ARID2 and the PBAF chromatin remodeling complex in hepatocellular carcinoma (2014) (2014)](https://doi.org/10.1016/j.jhep.2014.03.024)
[Vasileiou et al., Mutations in the BAF-complex subunit DPF2 are associated with Coffin-Siris syndrome (2018) (2018)](https://doi.org/10.1016/j.ajhg.2018.01.014)
[Mashtalir et al., Modular organization and assembly of SWI/SNF family chromatin remodeling complexes (2018) (2018)](https://doi.org/10.1016/j.cell.2018.09.032)
[Unknown, Kadoch & Crabtree, Mammalian SWI/SNF chromatin remodeling complexes and cancer (2015) (2015)](https://doi.org/10.1016/j.tig.2015.02.005)
[Hodges et al., Dominant-negative SMARCA4 mutants alter chromatin accessibility genome-wide (2018) (2018)](https://doi.org/10.1038/s41588-018-0263-x)
[Santen et al., Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients (2013) (2013)](https://doi.org/10.1002/humu.22394)
[Pan et al., PBAF loss alters enhancer chromatin landscape and cell identity during brain development (2021) (2021)](https://doi.org/10.1038/s41593-021-00876-w)
[Xu et al., ARID2 deficiency promotes tumor immune evasion via PBAF-dependent chromatin remodeling (2020) (2020)](https://doi.org/10.1016/j.ccell.2020.04.005)
[Mao et al., SWI/SNF chromatin remodeling complexes in neurodevelopmental and neurodegenerative disorders (2022) (2022)](https://doi.org/10.1016/j.tins.2022.04.002)
[Tsurusaki et al., Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome (2012) (2012)](https://doi.org/10.1038/ng.2219)