BRD3 (Bromodomain-Containing Protein 3)

BRD3 (Bromodomain-Containing Protein 3)

<div class="infobox infobox-gene">
<h3>BRD3</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Bromodomain-Containing Protein 3</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>BRD3</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>9q34.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[8019](https://www.ncbi.nlm.nih.gov/gene/8019)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[601541](https://omim.org/entry/601541)</td></tr>
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000169925](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000169925)</td></tr>
<tr><td><strong>UniProt</strong></td><td>[Q15059](https://www.uniprot.org/uniprot/Q15059)</td></tr>
<tr><td><strong>Protein</strong></td><td>Bromodomain-containing protein 3</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [Huntington's disease](/diseases/huntingtons-disease), NUT midline carcinoma</td></tr>
</table>
</div>

Overview

BRD3 (Bromodomain-Containing Protein 3)

<div class="infobox infobox-gene">
<h3>BRD3</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Bromodomain-Containing Protein 3</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>BRD3</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>9q34.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[8019](https://www.ncbi.nlm.nih.gov/gene/8019)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[601541](https://omim.org/entry/601541)</td></tr>
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000169925](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000169925)</td></tr>
<tr><td><strong>UniProt</strong></td><td>[Q15059](https://www.uniprot.org/uniprot/Q15059)</td></tr>
<tr><td><strong>Protein</strong></td><td>Bromodomain-containing protein 3</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [Huntington's disease](/diseases/huntingtons-disease), NUT midline carcinoma</td></tr>
</table>
</div>

Overview

BRD2 is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Gene Function

BRD3 encodes a member of the BET (Bromodomain and Extra-Terminal domain) family of chromatin readers, alongside [BRD2](/genes/brd2), [BRD4](/genes/brd4), and BRDT. BET proteins function as epigenetic readers that recognize and bind acetylated lysine residues on histones, serving as scaffolds to recruit transcriptional regulators to active chromatin [@filippakopoulos2010].

BRD3 is a 726-amino-acid protein containing:

• Bromodomains BD1 and BD2: Tandem bromodomains that recognize acetylated histones (particularly H4K5ac, H4K8ac, H4K12ac, and H3K14ac) and acetylated non-histone proteins
• Extra-terminal (ET) domain: Mediates protein–protein interactions with transcriptional co-regulators including NSD3, JMJD6, CHD4, and components of the ATAC and SWI/SNF chromatin remodeling complexes
• SEED motif: Phosphorylation-dependent regulatory region
• C-terminal domain (CTD): Unlike BRD4, BRD3 lacks the extended CTD that mediates P-TEFb recruitment, giving it distinct functional roles

• Transcriptional regulation: BRD3 promotes transcription from acetylated chromatin but does not directly recruit P-TEFb (unlike BRD4), instead facilitating RNA polymerase II passage through acetylated nucleosomal templates
• Hematopoietic transcription: BRD3 has a specialized role in GATA1-dependent erythroid gene expression, directly binding acetylated GATA1 to maintain erythroid transcriptional programs
• Chromatin bookmarking: BRD3 remains bound to acetylated mitotic chromosomes, facilitating rapid reactivation of transcription after cell division

Role in Neurodegeneration

Microglial Inflammatory Programs

BRD3 contributes to neuroinflammatory gene expression in [microglia](/cell-types/microglia-neuroinflammation), though with distinct target specificity compared to [BRD4](/genes/brd4). While BRD4 primarily drives super-enhancer-associated inflammatory genes, BRD3 preferentially regulates a subset of interferon-stimulated genes (ISGs) and complement pathway components. In [Alzheimer's disease](/diseases/alzheimers-disease) brain tissue, BRD3 protein levels are elevated in activated microglia surrounding [amyloid](/proteins/amyloid-beta) plaques [@shi2020].

BRD3 binds to acetylated chromatin at type I interferon response genes including IFITM3, OAS1, and ISG15, which are upregulated in disease-associated microglia (DAM). The BRD3-dependent interferon response contributes to the antiviral-like inflammatory state observed in AD microglia, which drives complement-mediated synapse elimination through C1q and C3 tagging [@lamonica2011].

Tau Acetylation and BET Protein Interactions

[Tau](/proteins/tau) protein is acetylated at multiple lysine residues in [Alzheimer's disease](/diseases/alzheimers-disease) and other tauopathies. Acetylated [tau](/proteins/tau) (ac-tau) can be recognized by BET bromodomains, creating aberrant BRD3–tau interactions that sequester BRD3 from its normal chromatin targets. This "epigenetic hijacking" by acetylated tau leads to transcriptional dysregulation in tauopathy-affected [neurons](/entities/neurons), as BRD3 is titrated away from neuronal gene promoters [@min2015].

BRD3's BD1 domain binds acetylated tau at K174 and K274, residues whose acetylation is increased in AD brain tissue. This interaction impairs BRD3's ability to maintain neuronal gene expression programs, contributing to the progressive transcriptional decline observed in affected neurons [@benner2020].

Huntington's Disease and Polyglutamine Expansion

In [Huntington's disease](/diseases/huntington-disease), mutant [huntingtin](/proteins/huntingtin) (mHTT) with expanded polyglutamine tracts disrupts BET protein function at multiple levels. mHTT sequesters histone acetyltransferases (particularly [CBP/CREBBP](/genes/crebbp)), reducing global histone acetylation and depleting the acetylated chromatin marks that BRD3 reads. Additionally, mHTT can directly interact with BRD3 and BRD4, impairing their chromatin association [@demars2019].

BET inhibitors paradoxically show benefit in HD models, likely because they release BRD3/4 from aberrant mHTT interactions, allowing compensatory redistribution of BET proteins to critical survival gene loci [@davies2018].

Oxidative Stress Response

BRD3 regulates the expression of antioxidant defense genes through its interaction with the NRF2–KEAP1 pathway. BRD3 binds to acetylated H3K27 at NRF2 target gene promoters, facilitating the transcription of [SOD2](/genes/sod2), [HMOX1](/genes/hmox1), NQO1, and glutathione biosynthesis enzymes. In neurodegeneration, where oxidative stress is a major pathogenic driver, BRD3 dysfunction impairs the cellular antioxidant response, increasing neuronal vulnerability to [reactive oxygen species](/entities/reactive-oxygen-species) [@gilan2020].

Expression in the Nervous System

BRD3 is expressed throughout the brain, with highest levels in the cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), thalamus, and cerebellum. Expression is broadly distributed across neuronal and glial cell types, with moderate levels in oligodendrocytes and [astrocytes](/entities/astrocytes) and lower levels in microglia (where BRD3 is upregulated upon activation) [@sartor2019].

During neural development, BRD3 is expressed at moderate levels during neurogenesis and increases during the period of synaptogenesis and myelination. In the adult brain, BRD3 expression remains stable across aging, unlike BRD4 which shows age-related decline in some regions. However, BRD3 protein levels increase in AD-affected hippocampal tissue, likely reflecting glial proliferation and activation [@nicodeme2010].

Single-nucleus RNA sequencing from human AD brain tissue shows upregulation of BRD3 in disease-associated microglia and reactive astrocytes, while expression in neurons is relatively preserved.

Common Variants and Disease Associations

| Variant | Type | Association | Reference |
|---------|------|-------------|-----------|
| rs10987022 | SNP (intronic) | Nominal association with cognitive decline | [Davies et al., 2018](https://doi.org/10.1038/s41467-018-04362-x) |
| BRD3–NUT fusion | Translocation | NUT midline carcinoma (not neurodegeneration) | [French et al., 2008](https://doi.org/10.1038/onc.2008.20) |
| 9q34 microdeletion | CNV | Intellectual disability, Kleefstra syndrome region | [Kleefstra et al., 2009](https://doi.org/10.1086/595764) |

Therapeutic Implications

BRD3 is a target of pan-BET inhibitors and increasingly of selective modulators:

• Pan-BET inhibitors (JQ1, I-BET762, OTX015): Block all BET protein bromodomains, including BRD3. These compounds reduce neuroinflammation and show benefit in AD, PD, and HD animal models, but cause dose-limiting toxicities due to BRD4 inhibition.
• BD1-selective inhibitors (GSK778, olinone): Preferentially target the BD1 bromodomain shared by BRD2/3/4. BD1 inhibition shows anti-inflammatory effects with reduced hematopoietic toxicity compared to pan-BET inhibition.
• BD2-selective inhibitors (ABBV-744, apabetalone/RVX-208): Target the BD2 bromodomain, showing selectivity for BRD3/BRD4 BD2. Apabetalone (RVX-208) is in clinical trials for cardiovascular disease and shows potential for neuroinflammatory conditions.
• BRD3-selective degraders: PROTAC-based approaches to selectively degrade BRD3 while preserving BRD4 transcriptional function, potentially offering a therapeutic window for neuroinflammation without pan-BET toxicity.

See Also

• [BRD2](/genes/brd2) — BET family member, epilepsy association
• [BRD4](/genes/brd4) — BET family member, super-enhancer regulation
• [NSD3](/genes/nsd3) — BET-interacting methyltransferase
• [CREBBP](/genes/crebbp) — histone acetyltransferase, Huntington's disease
• [KDM4A](/genes/kdm4a) — histone demethylase
• [Epigenetic Mechanisms in Neurodegeneration](/mechanisms/epigenetic-mechanisms)
• [Neuroinflammation](/mechanisms/neuroinflammation)

External Links

• [NCBI Gene: BRD3](https://www.ncbi.nlm.nih.gov/gene/8019)
• [UniProt: Q15059](https://www.uniprot.org/uniprot/Q15059)
• [GeneCards: BRD3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=BRD3)
• [OMIM: 601541](https://omim.org/entry/601541)
• [Allen Brain Atlas: BRD3](https://portal.brain-map.org/explore/genes?searchTerm=BRD3)

References