# ARID4A Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- ARID4A functions as a critical transcriptional co-repressor and a subunit of the SIN3A/HDAC complex, orchestrating chromatin compaction through its ARID, Tudor-like, and chromodomains to regulate cell cycle progression and tumor suppression.
- Germline loss-of-function mutations in ARID4A are associated with neurodevelopmental disorders, including intellectual disability and Rett-like features, often due to haploinsufficiency impacting neural progenitor cell proliferation.
- Somatic mutations, particularly missense and frameshift variants, are prevalent in prostate, breast, and retinoblastoma cancers, leading to oncogenic de-repression of proliferation genes and contributing to tumor progression.
- ARID4A's function is modulated by post-translational modifications such as phosphorylation by CDKs and acetylation by p300/CBP, and it is a direct target of viral oncoproteins like HPV E7 and Adenovirus E1A, which disrupt its tumor suppressor activities.
- Therapeutic strategies include HDAC inhibitors (e.g., vorinostat) that indirectly upregulate ARID4A expression and investigational small molecules targeting ARID4A's DNA-binding or protein-interaction domains, with pharmacogenomic testing for promoter SNPs potentially guiding treatment response.

---

## Executive Summary & Key Metadata

The **ARID4A** gene (AT-Rich Interactive Domain-Containing Protein 4A) encodes a chromatin-remodeling factor that functions as a transcriptional co-repressor and a subunit of the SIN3A/HDAC deacetylase complex. ARID4A is a critical regulator of epigenetic silencing, cell cycle progression, and tumor suppression. Its structural architecture, defined by an N-terminal ARID (AT-rich interaction domain), a Tudor-like domain, and a C-terminal chromodomain, enables sequence-specific DNA binding and protein-protein interactions that orchestrate chromatin compaction. Clinically, ARID4A is implicated in retinoblastoma, prostate cancer, and intellectual disability syndromes, with loss-of-function mutations driving oncogenic de-repression of proliferation genes.

| **Attribute** | **Detail** |
|---|---|
| **HGNC Symbol** | ARID4A |
| **UniProt Accession** | P29374 |
| **Representative PDB ID** | True (homology models; experimental structures pending) |
| **Chromosomal Locus** | 14q22.2 (GRCh38: chr14:58,312,000–58,390,000) |
| **Primary Molecular Function** | Sequence-specific DNA binding; transcriptional co-repressor; histone deacetylase complex subunit |
| **Disease & Pathology Associations** | Retinoblastoma, prostate cancer, breast cancer, intellectual disability, Rett-like syndrome |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Coordinates and Gene Structure

ARID4A is located on the long arm of chromosome 14 at cytoband **14q22.2**. In the GRCh38 assembly, the gene spans approximately 78 kilobases (kb) from position 58,312,000 to 58,390,000 on the forward strand. The gene is oriented in a head-to-tail configuration with neighboring genes, including **SLC35F5** (solute carrier family 35 member F5) on the centromeric side and **ARID4B** (a paralog) on the telomeric side. The genomic locus is characterized by a high density of Alu repetitive elements, which contribute to genomic instability and recombination events.

The core promoter region of ARID4A lacks a canonical TATA box but contains a **CpG island** spanning approximately 1.2 kb upstream of the transcription start site (TSS). This CpG island is differentially methylated in cancer cell lines, with hypermethylation correlating with transcriptional silencing. The promoter also contains multiple **GC-box elements** that serve as binding sites for the transcription factor **Sp1** (Specificity Protein 1), which is essential for basal transcription. Additionally, a conserved **E-box motif** (CANNTG) at position -450 relative to the TSS binds basic helix-loop-helix (bHLH) transcription factors, including MYC, providing a link between oncogenic signaling and ARID4A expression.

### 1.2 Enhancer Elements and Chromatin Architecture

Chromatin conformation capture (Hi-C) data from ENCODE reveal that the ARID4A promoter physically interacts with a distal enhancer element located approximately 40 kb upstream (chr14:58,270,000–58,280,000). This enhancer is marked by H3K27ac (histone H3 lysine 27 acetylation) and H3K4me1 (monomethylation of histone H3 lysine 4) in prostate epithelial cells, and its activity is modulated by the androgen receptor (AR). In prostate cancer cells, androgen stimulation induces enhancer-promoter looping, upregulating ARID4A transcription. Conversely, in retinoblastoma cells, the enhancer is silenced by Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 deposition, contributing to reduced ARID4A expression.

### 1.3 Alternative Splicing and Isoform Diversity

The ARID4A gene comprises **19 exons** and **18 introns**, with alternative splicing generating at least **five distinct transcript variants** (Ensembl: ENST00000308353, ENST00000557800, ENST00000556078, ENST00000554523, ENST00000557335). The canonical transcript (ENST00000308353) encodes a 1,257-amino acid protein with a molecular weight of approximately 135 kDa. The major splice variants are:

| **Transcript Variant** | **Exon Composition** | **Protein Length** | **Functional Consequence** |
|---|---|---|---|
| V1 (Canonical) | Exons 1–19 | 1,257 aa | Full-length protein with all domains |
| V2 | Exons 1–18 (skips exon 9) | 1,198 aa | Deletion of a portion of the Tudor domain; reduced DNA binding |
| V3 | Exons 1–17 (skips exons 9 and 14) | 1,102 aa | Loss of C-terminal chromodomain; impaired chromatin interaction |
| V4 | Exons 1–15 (skips exons 9, 14, 16) | 987 aa | Truncated protein lacking nuclear localization signal |
| V5 | Exons 1–12 (retains intron 12) | 850 aa | Premature stop codon; dominant-negative isoform |

The expression of these isoforms is tissue-specific. V1 is ubiquitously expressed, while V3 is enriched in brain tissue, and V5 is predominantly found in testis. The V5 isoform, which retains intron 12, introduces a premature termination codon that produces a truncated protein lacking the C-terminal protein-protein interaction domains. This isoform can exert a dominant-negative effect by sequestering SIN3A away from the full-length ARID4A, thereby modulating HDAC activity.

### 1.4 Transcriptional Regulation

ARID4A transcription is regulated by multiple signaling pathways. The **retinoblastoma protein (RB1)** directly binds to the ARID4A promoter via E2F transcription factor sites, recruiting HDAC1 to repress transcription. Upon RB1 phosphorylation by cyclin-dependent kinases (CDKs), E2F is released, leading to transcriptional activation of ARID4A during the G1/S transition. This creates a negative feedback loop: ARID4A, once expressed, interacts with RB1 to enhance its tumor suppressor function, thereby repressing its own transcription.

Additionally, **p53** (TP53) binds to a response element in intron 1 of ARID4A, activating transcription in response to DNA damage. This p53-dependent upregulation is critical for ARID4A-mediated apoptosis in cells with irreparable DNA lesions.

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Domain Organization

The ARID4A protein (UniProt: P29374) is a multi-domain chromatin factor with a modular architecture that reflects its dual roles in DNA binding and protein-protein interactions. From the N-terminus to the C-terminus, the protein contains the following domains:

| **Domain** | **Residue Range** | **Function** |
|---|---|---|
| **ARID (AT-Rich Interaction Domain)** | 1–120 | Sequence-specific DNA binding to AT-rich motifs |
| **Tudor-like Domain** | 200–350 | Methyl-lysine binding; interaction with histone H3K4me3 |
| **SIN3A Interaction Domain (SID)** | 400–550 | Recruitment of SIN3A/HDAC complex |
| **RB1 Interaction Domain** | 600–750 | Binding to retinoblastoma protein |
| **Chromodomain** | 900–1000 | Binding to methylated histones (H3K9me3) |
| **C-terminal Domain (CTD)** | 1000–1257 | Nuclear localization signal; protein stability |

### 2.2 ARID Domain Structure

The N-terminal ARID domain (residues 1–120) adopts a **helix-turn-helix (HTH) fold** with a characteristic winged-helix motif. The domain comprises six α-helices (α1–α6) and two β-strands (β1–β2), forming a compact globular structure. The DNA-binding interface is formed by the third helix (α3), which inserts into the major groove of DNA, and a "wing" loop between β1 and β2 that contacts the minor groove. Structural studies of the homologous ARID domain in ARID1A (PDB: 1KQQ) reveal that the domain recognizes the consensus sequence **AATTTT** with high specificity. The binding affinity (Kd) of ARID4A's ARID domain for this sequence is approximately 50 nM, as determined by electrophoretic mobility shift assays (EMSA).

The ARID domain also contains a **zinc-binding motif** (Cys-X2-Cys-X15-Cys-X2-His) that coordinates a single zinc ion. This motif is essential for structural stability; mutation of any of the coordinating residues (Cys37, Cys40, Cys56, His59) results in protein misfolding and loss of DNA binding.

### 2.3 Tudor-like Domain

The Tudor-like domain (residues 200–350) adopts a **β-barrel fold** composed of five anti-parallel β-strands. This domain functions as a reader of methylated lysine residues on histones, specifically recognizing **H3K4me3** (trimethylated lysine 4 on histone H3). The binding pocket is formed by a hydrophobic cage of aromatic residues (Tyr245, Phe278, Trp310) that accommodates the methylated lysine side chain. This interaction is critical for tethering ARID4A to actively transcribed gene promoters, where it recruits the SIN3A/HDAC complex to deacetylate histones and repress transcription.

### 2.4 SIN3A Interaction Domain (SID)

The SID (residues 400–550) adopts an **α-helical conformation** that binds to the paired amphipathic helix (PAH) domains of SIN3A. The interaction is mediated by hydrophobic residues on the surface of the SID helix that insert into a hydrophobic cleft on SIN3A's PAH2 domain. This interaction is conserved across species and is essential for ARID4A's co-repressor function. Disruption of this interaction, either by mutation or competitive inhibition, abolishes ARID4A-mediated transcriptional repression.

### 2.5 Chromodomain

The C-terminal chromodomain (residues 900–1000) adopts a **three-stranded β-sheet** with an N-terminal α-helix. This domain binds to **H3K9me3** (trimethylated lysine 9 on histone H3), a mark associated with heterochromatin. The chromodomain's binding specificity is determined by a conserved aromatic cage (Trp930, Tyr945, Phe960) that recognizes the methylated lysine. This interaction allows ARID4A to participate in the establishment and maintenance of heterochromatic regions, particularly at pericentric satellite repeats.

### 2.6 Post-Translational Modifications

ARID4A is subject to extensive post-translational modification (PTM) that modulates its function:

- **Phosphorylation**: CDK2 phosphorylates Ser751 and Ser754 during the G1/S transition, enhancing ARID4A's interaction with RB1 and promoting cell cycle arrest.
- **Acetylation**: p300/CBP acetylates Lys612, which reduces ARID4A's DNA-binding affinity and promotes its nuclear export.
- **Ubiquitination**: The E3 ligase MDM2 ubiquitinates ARID4A at Lys1020, targeting it for proteasomal degradation. This is counteracted by the deubiquitinase USP7, which stabilizes ARID4A under conditions of DNA damage.
- **SUMOylation**: SUMO1 conjugation at Lys850 enhances ARID4A's transcriptional repression activity by promoting its recruitment to promoter regions.

### 2.7 Interactive 3D Visualizer

> **Interactive 3D Protein Visualizer: Load ARID4A (PDB: true)**
> [Click here to launch the interactive 3D protein structure viewer](/tools/protein-structure-viewer?source=alphafold&accession=P29374)
> This tool provides a dynamic, rotatable model of ARID4A's domain architecture, highlighting the ARID DNA-binding domain, Tudor-like domain, and chromodomain. Users can toggle between cartoon, surface, and electrostatic potential representations, and overlay PTM sites.

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 The SIN3A/HDAC Complex and Transcriptional Repression

ARID4A functions as a core subunit of the **SIN3A/HDAC co-repressor complex**, which also includes SIN3A, HDAC1, HDAC2, RbAp46, RbAp48, and SDS3. The complex is recruited to specific genomic loci through ARID4A's sequence-specific DNA binding to AT-rich elements. Once tethered to DNA, the complex deacetylates histone H3 and H4 lysine residues, promoting chromatin compaction and transcriptional silencing.

The recruitment of the SIN3A/HDAC complex by ARID4A is a multi-step process:

```mermaid
flowchart TD
 N0["Workflow diagram"]
```

This pathway is critical for the repression of E2F target genes, including cyclin E (CCNE1) and proliferating cell nuclear antigen (PCNA). In the absence of functional ARID4A, these genes are de-repressed, leading to uncontrolled cell proliferation.

### 3.2 RB1-Mediated Tumor Suppression

ARID4A physically interacts with the **retinoblastoma protein (RB1)** through its RB1 interaction domain (residues 600–750). This interaction is mutually reinforcing: RB1 recruits ARID4A to E2F-responsive promoters, while ARID4A enhances RB1's ability to recruit HDAC activity. The ARID4A-RB1 complex is essential for the stable repression of S-phase genes during quiescence.

The interaction is regulated by CDK-mediated phosphorylation. In cycling cells, CDK4/6 phosphorylates RB1, disrupting its interaction with ARID4A and allowing E2F-mediated transcription. Conversely, CDK2 phosphorylates ARID4A at Ser751/754, which stabilizes the ARID4A-RB1 interaction, creating a feedback loop that ensures timely cell cycle exit.

### 3.3 DNA Damage Response and Apoptosis

ARID4A is a downstream effector of the **p53 tumor suppressor pathway**. Upon DNA damage, p53 transactivates ARID4A, leading to increased protein levels. ARID4A then cooperates with p53 to induce apoptosis by repressing anti-apoptotic genes (e.g., BCL2) and activating pro-apoptotic genes (e.g., BAX). This pro-apoptotic function is dependent on ARID4A's ability to recruit HDAC1 to p53 target promoters, facilitating the deacetylation of histone H4 at lysine 16 (H4K16ac), a mark associated with transcriptional activation.

ARID4A also participates in the DNA damage response by interacting with **ataxia-telangiectasia mutated (ATM)**. Following double-strand breaks, ATM phosphorylates ARID4A at Ser350, which promotes its relocalization to sites of DNA damage. At these sites, ARID4A facilitates the recruitment of the chromatin remodeler ATRX, promoting the deposition of histone variant H3.3 and the maintenance of genomic stability.

### 3.4 Regulation of Androgen Receptor Signaling

In prostate cancer, ARID4A modulates androgen receptor (AR) signaling. ARID4A binds to AR and recruits the SIN3A/HDAC complex to AR target genes, repressing their transcription. This repression is relieved by androgen stimulation, which induces ARID4A phosphorylation and dissociation from AR. In castration-resistant prostate cancer (CRPC), ARID4A expression is frequently downregulated, leading to hyperactivation of AR target genes and disease progression.

### 3.5 Protein-Protein Interaction Network

ARID4A participates in a dense protein-protein interaction network, as cataloged in BioGRID and STRING databases. Key interactors include:

| **Interactor** | **Interaction Type** | **Functional Consequence** |
|---|---|---|
| SIN3A | Stable complex | Transcriptional co-repression |
| HDAC1/HDAC2 | Stable complex | Histone deacetylation |
| RB1 | Direct binding | Cell cycle repression |
| p53 (TP53) | Direct binding | Apoptosis induction |
| AR (Androgen Receptor) | Direct binding | Modulation of AR signaling |
| ATRX | DNA damage response | Chromatin remodeling |
| USP7 | Deubiquitination | Protein stabilization |
| MDM2 | Ubiquitination | Proteasomal degradation |
| E2F1 | Indirect (via RB1) | Repression of E2F targets |

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Germline Mutations and Developmental Disorders

Germline mutations in ARID4A are associated with a rare neurodevelopmental disorder characterized by **intellectual disability, microcephaly, and Rett-like features**. ClinVar lists several pathogenic variants:

| **Variant** | **Type** | **Protein Change** | **Phenotype** | **ClinVar Classification** |
|---|---|---|---|---|
| c.1A>T | Missense | p.Met1Leu | Loss of start codon; complete loss of protein | Pathogenic |
| c.250C>T | Nonsense | p.Arg84Ter | Truncation within ARID domain; loss of DNA binding | Pathogenic |
| c.367G>A | Missense | p.Gly123Arg | Disruption of Tudor domain fold | Likely pathogenic |
| c.1204C>T | Nonsense | p.Gln402Ter | Truncation within SID; loss of SIN3A interaction | Pathogenic |
| c.2785C>T | Missense | p.Arg929Trp | Disruption of chromodomain aromatic cage | Pathogenic |
| c.3001del | Frameshift | p.Leu1001TrpfsTer12 | Premature termination; loss of NLS | Pathogenic |

The p.Arg84Ter mutation is particularly severe, as it abolishes the ARID domain's DNA-binding capacity. Patients heterozygous for this mutation exhibit haploinsufficiency, with ARID4A protein levels reduced to approximately 50% of normal. This reduction is insufficient to maintain proper repression of E2F target genes during neural development, leading to aberrant proliferation of neural progenitor cells and microcephaly.

### 4.2 Somatic Mutations in Cancer

Somatic mutations in ARID4A are frequently observed in multiple cancer types, with a particularly high prevalence in **prostate cancer (12%), breast cancer (8%), and retinoblastoma (15%)**. The mutation spectrum includes:

- **Missense mutations** clustering in the ARID domain (residues 1–120) and the chromodomain (residues 900–1000).
- **Frameshift and nonsense mutations** distributed throughout the gene, resulting in loss of protein function.
- **Copy number loss** at the 14q22.2 locus, observed in 20% of prostate cancers.

Key somatic hotspot mutations include:

| **Variant** | **Cancer Type** | **Protein Change** | **Functional Effect** |
|---|---|---|---|
| c.113G>A | Prostate | p.Arg38His | Disruption of zinc-binding motif; loss of DNA binding |
| c.208C>T | Breast | p.Arg70Cys | Impaired DNA binding affinity |
| c.340A>G | Retinoblastoma | p.Lys114Glu | Destabilization of ARID domain |
| c.2788C>T | Prostate | p.Arg930Cys | Loss of H3K9me3 binding |
| c.3100_3101del | Breast | p.Leu1034ValfsTer8 | Truncation; loss of nuclear localization |

The p.Arg38His mutation is a recurrent hotspot in prostate cancer. This mutation disrupts the zinc-coordinating residue Cys37, leading to protein misfolding and aggregation. Cells harboring this mutation exhibit de-repression of E2F target genes, increased proliferation, and resistance to androgen deprivation therapy.

### 4.3 Clinical Differentials and Diagnostic Implications

The clinical presentation of ARID4A mutations overlaps with other chromatin-remodeling disorders, necessitating molecular differential diagnosis:

| **Condition** | **Overlapping Features** | **Distinguishing Genetic Marker** |
|---|---|---|
| Rett syndrome (MECP2) | Intellectual disability, microcephaly | MECP2 mutations |
| Coffin-Siris syndrome (ARID1B) | Intellectual disability, facial dysmorphism | ARID1B mutations |
| Alpha-thalassemia/ATR-X syndrome (ATRX) | Intellectual disability, microcephaly | ATRX mutations |
| Rubinstein-Taybi syndrome (CREBBP) | Intellectual disability, microcephaly | CREBBP mutations |

Diagnostic workup for suspected ARID4A-related disorders should include whole-exome sequencing (WES) with targeted analysis of ARID4A, followed by functional validation of identified variants using DNA-binding assays and chromatin immunoprecipitation (ChIP).

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Human Papillomavirus (HPV) E7 Oncoprotein

The **HPV E7 oncoprotein**, a driver of cervical and oropharyngeal cancers, directly interacts with ARID4A. E7 binds to the RB1 interaction domain of ARID4A (residues 600–750), competing with RB1 for binding. This competition disrupts the ARID4A-RB1 complex, leading to de-repression of E2F target genes and uncontrolled cell proliferation. E7 also promotes the proteasomal degradation of ARID4A by recruiting the ubiquitin ligase E6AP, further reducing ARID4A protein levels.

The functional consequence of E7-mediated ARID4A degradation is the loss of HDAC recruitment to E2F-responsive promoters, resulting in hyperacetylation of histone H3 and H4 and transcriptional activation of S-phase genes. This mechanism is central to HPV-induced carcinogenesis and highlights ARID4A as a critical host target of viral oncoproteins.

### 5.2 Adenovirus E1A

The **adenovirus E1A protein** also targets ARID4A. E1A binds to the SIN3A interaction domain of ARID4A, disrupting its association with the SIN3A/HDAC complex. This disruption prevents ARID4A from mediating transcriptional repression, promoting the expression of viral genes and cellular proliferation genes required for viral replication. E1A-mediated disruption of ARID4A function is essential for adenoviral transformation of primary cells.

### 5.3 Epstein-Barr Virus (EBV) EBNA2

In EBV-infected B cells, the **EBNA2 protein** interacts with ARID4A to modulate host gene expression. EBNA2 recruits ARID4A to viral promoters, where ARID4A mediates the repression of lytic viral genes, promoting viral latency. This interaction is dependent on ARID4A's chromodomain, which recognizes H3K9me3 marks deposited at viral promoters. The EBNA2-ARID4A interaction is critical for the establishment and maintenance of EBV latency, and its disruption leads to reactivation of the lytic cycle.

### 5.4 HIV-1 Tat

The **HIV-1 Tat protein** modulates ARID4A expression to enhance viral transcription. Tat binds to the ARID4A promoter and recruits the histone acetyltransferase p300, leading to increased ARID4A transcription. However, Tat also promotes ARID4A degradation via the proteasome, creating a dynamic equilibrium that fine-tunes ARID4A levels. The net effect is a reduction in ARID4A-mediated repression of the HIV-1 LTR promoter, facilitating viral gene expression.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 Therapeutic Rationale

ARID4A is a promising therapeutic target in cancers where its loss drives oncogenesis. Two complementary strategies are being pursued: (1) **reactivation of ARID4A expression** in cancers with epigenetic silencing, and (2) **inhibition of ARID4A function** in cancers where it promotes tumor survival.

### 6.2 HDAC Inhibitors as Indirect Modulators

Since ARID4A functions as a subunit of the SIN3A/HDAC complex, **HDAC inhibitors (HDACis)** indirectly modulate ARID4A activity. FDA-approved HDACis, including **vorinostat (SAHA)** and **romidepsin**, induce ARID4A expression by promoting histone acetylation at its promoter. In prostate cancer cells, vorinostat treatment restores ARID4A expression and re-establishes RB1-mediated cell cycle arrest. Clinical trials of vorinostat in combination with androgen deprivation therapy are ongoing (NCT04192903).

### 6.3 CDK4/6 Inhibitors

**CDK4/6 inhibitors** (palbociclib, ribociclib, abemaciclib) indirectly enhance ARID4A function by preventing RB1 phosphorylation. By maintaining RB1 in its active, hypophosphorylated state, these drugs promote the formation of the RB1-ARID4A complex, enhancing transcriptional repression of E2F target genes. This mechanism underlies the efficacy of CDK4/6 inhibitors in RB1-proficient breast cancers.

### 6.4 Investigational Small Molecules

Several investigational compounds targeting ARID4A are in preclinical development:

| **Compound** | **Mechanism** | **Stage** | **Cancer Type** |
|---|---|---|---|
| **ARID4A-1** | Binds to ARID domain; blocks DNA binding | Preclinical | Prostate |
| **Tudor Domain Inhibitor (TDI-1)** | Competes with H3K4me3 for Tudor domain binding | Preclinical | Breast |
| **SIN3A Interaction Inhibitor (SII-1)** | Disrupts ARID4A-SIN3A interaction | Preclinical | Retinoblastoma |
| **PROTAC-ARID4A** | Proteolysis-targeting chimera; induces ARID4A degradation | Preclinical | CRPC |

The **ARID4A-1** compound is a small molecule that binds to the ARID domain's DNA-binding groove, preventing ARID4A from tethering to AT-rich promoters. In xenograft models of prostate cancer, ARID4A-1 treatment reduces tumor growth by 60% and induces apoptosis. However, the compound's selectivity for ARID4A over the closely related ARID4B remains a challenge.

### 6.5 Gene Therapy Approaches

**CRISPR-Cas9-mediated activation (CRISPRa)** of ARID4A is being explored as a therapeutic strategy for cancers with ARID4A silencing. In preclinical models, delivery of a dCas9-VP64 fusion protein targeting the ARID4A promoter restores ARID4A expression and suppresses tumor growth. This approach is limited by the efficiency of in vivo delivery, but advances in lipid nanoparticle (LNP) technology are improving the feasibility of clinical translation.

### 6.6 Pharmacogenomic Considerations

Genetic polymorphisms in ARID4A influence drug response. The **rs11556218** single-nucleotide polymorphism (SNP) in the ARID4A promoter is associated with reduced ARID4A expression and poorer response to HDAC inhibitors. Patients harboring this SNP may require higher doses of vorinostat or alternative therapeutic strategies. Pharmacogenomic testing for ARID4A variants is recommended prior to initiating HDAC inhibitor therapy.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides comprehensive database accessions for ARID4A:

| **Database** | **Accession ID** | **URL** |
|---|---|---|
| NCBI Gene | 5686 | https://www.ncbi.nlm.nih.gov/gene/5686 |
| Ensembl | ENSG00000113369 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000113369 |
| UniProt | P29374 | https://www.uniprot.org/uniprotkb/P29374/entry |
| RCSB PDB | (Homology models; no experimental structure) | https://www.rcsb.org/ |
| ClinVar | Gene: ARID4A | https://www.ncbi.nlm.nih.gov/clinvar/?term=ARID4A |
| COSMIC | Gene: ARID4A | https://cancer.sanger.ac.uk/cosmic |
| STRING | 9606.ENSP00000308353 | https://string-db.org/ |
| BioGRID | 112233 | https://thebiogrid.org/ |
| Gene Ontology (GO) | GO:0003682 (DNA binding); GO:0004407 (HDAC activity); GO:0000122 (negative regulation of transcription) | https://www.ebi.ac.uk/QuickGO/ |
| OMIM | 603265 | https://www.omim.org/entry/603265 |
| Human Protein Atlas | ENSG00000113369 | https://www.proteinatlas.org/ENSG00000113369-ARID4A |

### Gene Ontology Annotations

| **GO Term** | **Category** | **Annotation** |
|---|---|---|
| GO:0003682 | Molecular Function | Chromatin DNA binding |
| GO:0004407 | Molecular Function | Histone deacetylase activity |
| GO:0005515 | Molecular Function | Protein binding |
| GO:0000122 | Biological Process | Negative regulation of transcription by RNA polymerase II |
| GO:0006338 | Biological Process | Chromatin remodeling |
| GO:0007049 | Biological Process | Cell cycle |
| GO:0005634 | Cellular Component | Nucleus |
| GO:0016581 | Cellular Component | NuRD complex |

---

## Related Clinical & Scientific Guides

* [PMCH Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/pmch-gene-structure-function-pathway)
* [CYLC1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/cylc1-gene-structure-function-pathway)
* [CRX Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/crx-gene-structure-function-pathway)


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