PHF23 — PHD Finger Protein 23

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PHF23 — PHD Finger Protein 23

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PHF23 — PHD Finger Protein 23</th>
</tr>
<tr>
<td class="label">Complex</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">HDAC complexes</td>
<td>Recruitment</td>
</tr>
<tr>
<td class="label">HMT complexes</td>
<td>Recruitment</td>
</tr>
<tr>
<td class="label">SWI/SNF</td>
<td>Chromatin remodeling</td>
</tr>
<tr>
<td class="label">LSD1/CoREST</td>
<td>Histone demethylation</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>High</td>
</tr>
<tr>
<td class="label">Ovary</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">HDAC1/2</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">LSD1</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">REST</td>
<td>Co-repressor</td>
</tr>
<tr>
<td class="label">CoREST</td>
<td>Complex</td>
</tr>
<tr>
<td class="label">BRAF35</td>
<td>Chromatin</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>PHF23 Role</td>
</tr>
<tr>
<td c

...

PHF23 — PHD Finger Protein 23

Overview

PHF23 (PHD Finger Protein 23) is a nuclear chromatin-binding protein that functions as an epigenetic "reader" by recognizing specific histone modifications through its Plant Homeodomain (PHD) zinc finger. The PHF23 gene (ENSG00000116161) is located on chromosome 17p13.1 and encodes a protein of 445 amino acids. This small protein plays crucial roles in gene regulation, developmental biology, and increasingly recognized functions in neuronal biology and neurodegeneration [1](https://pubmed.ncbi.nlm.nih.gov/30606451/).

Epigenetic regulation—heritable changes in gene expression without alterations to the DNA sequence—has emerged as a critical area of investigation in neurodegenerative diseases. Histone modifications, DNA methylation, and chromatin remodeling all contribute to the precise temporal and spatial control of gene expression necessary for neuronal survival and function. PHF23, as a histone reader protein, bridges the recognition of specific histone marks to the recruitment of effector complexes that modulate chromatin state and gene transcription [2](https://pubmed.ncbi.nlm.nih.gov/29581211/).

Dysregulation of epigenetic machinery has been documented in multiple neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). PHF23 and related PHD finger proteins represent potential therapeutic targets for modulating these epigenetic changes and potentially slowing or reversing neurodegeneration.

Molecular Biology and Structure

Gene Organization

The PHF23 gene spans approximately 4.5 kb of genomic DNA and comprises 6 exons. It encodes a protein of 445 amino acids with a molecular weight of approximately 48 kDa. The gene is located on chromosome 17p13.1, a region frequently altered in various neurological conditions.

Protein Domain Architecture

PHF23 contains several functional domains:

PHD Finger Domain (C-terminal)

C4HC3-type zinc finger motif
~50 amino acids in length
Binds histone H3 tails
Recognizes H3K4me0/3 methylation states
Critical for chromatin targeting

N-terminal Region

Proline-rich sequences
Regulatory phosphorylation sites
Potential protein-protein interaction motifs

Nuclear Localization Signal (NLS)

Basic amino acid cluster
Directs nuclear import
Essential for function

Structural Features

The PHD finger of PHF23 adopts a distinct structural fold:

Zinc-finger coordinated by Cys/His residues
Binding pocket for histone N-terminal tail
Surface for protein-protein interactions
Specificity for unmodified or methylated H3

Structural studies reveal:

Aromatic cage for methyl-lysine recognition
Hydrogen bonding network for histone contacts
Conformational flexibility for different substrates

Function in Cellular Physiology

Histone Recognition and Epigenetic Reading

The primary function of PHF23 is to serve as an epigenetic reader—a protein that recognizes specific histone modifications and translates them into downstream biological effects. This process involves:

Histone binding: PHD domain binds to histone H3 tails

Modification recognition: Distinguishes between methylated and unmodified states

Effector recruitment: Recruits chromatin-modifying complexes

Gene regulation: Modulates transcription of target genes

PHF23 exhibits specificity for:

H3K4me0: Unmethylated—often associated with silent chromatin
H3K4me3: Trimethylated—associated with active promoters
H3K9me3: Heterochromatin marks
H3K27me3: Polycomb-mediated repression

Chromatin Complex Recruitment

PHF23 interacts with multiple chromatin-associated complexes:

Transcriptional Regulation

PHF23 modulates gene expression through:

Promoter targeting: Directs complexes to specific loci
Enhancer interaction: Modulates enhancer activity
Developmental genes: Critical for development
Immediate-early genes: Rapid response to signals

Neuronal Function

In neurons, PHF23 regulates:

Synaptic plasticity genes: Immediate-early gene expression
Neuronal activity: Response to depolarization
Development: Neuronal differentiation
Survival factors: Anti-apoptotic gene expression

Disease Associations

Alzheimer's Disease (AD)

PHF23 is implicated in AD pathogenesis through multiple mechanisms [3](https://pubmed.ncbi.nlm.nih.gov/29157504/):

Histone modification changes:

Altered H3K4me3 in AD brains
Dysregulated H3K27me3 patterns
Impaired histone acetylation

Transcriptional dysfunction:

Reduced expression of synaptic proteins
Altered immediate-early gene responses
Dysregulated stress response genes

Therapeutic implications:

HDAC inhibitors restore function
Epigenetic therapy approaches
PHD finger targeting

Parkinson's Disease (PD)

PHF23 contributes to PD through:

Dopaminergic neuron vulnerability:

Altered chromatin states in substantia nigra
Dysregulated survival genes
Impaired stress responses

α-Synuclein toxicity:

Epigenetic regulation of SNCA
Histone changes in PD models
Therapeutic targeting potential

Huntington's Disease (HD)

PHF23 and related proteins:

Transcriptional dysregulation in HD
Histone modifications altered
Polyglutamine effects on chromatin

Amyotrophic Lateral Sclerosis (ALS)

Epigenetic changes in ALS:

Motor neuron-specific alterations
Dysregulated chromatin remodeling
Therapeutic targeting potential

Cancer

PHF23 altered in various cancers:

Altered expression in leukemia
Lymphoma associations
Prognostic significance

Expression Pattern

Tissue Distribution

Brain Regional Expression

Within the brain, PHF23 is expressed in:

Cerebral cortex: All layers
Hippocampus: CA regions, dentate gyrus
Cerebellum: Purkinje cells
Basal ganglia: Striatum
Substantia nigra: Dopaminergic neurons
Spinal cord: Motor neurons

Cellular Localization

PHF23 localizes:

Nucleus: Primary location
Chromatin: Bound to histone complexes
Nucleolus: Some associations
Promoter/enhancer regions: Genomic targeting

Therapeutic Implications

Epigenetic Therapy

Targeting PHF23 and related proteins:

HDAC inhibitors

Vorinostat (SAHA)
Trichostatin A
Valproic acid

Histone methyltransferase inhibitors

DOT1L inhibitors
PRDM inhibitors

PHD finger modulators

Small molecule activators/inhibitors
Peptide-based approaches

Combination Approaches

HDAC + HMT inhibitors: Combined epigenetic therapy
Epigenetic + gene therapy: Multi-target approaches
Epigenetic + neuroprotective: Disease modification

Biomarker Potential

PHF23 expression as:

Disease biomarker: Diagnostic potential
Treatment response: Therapeutic monitoring
Prognostic indicator: Outcome prediction

Interactions and Pathways

Protein Interactions

PHF23 interacts with:

Signaling Pathways

Target Genes

PHF23 regulates:

Synaptic genes: Synapsin, PSD95
Activity-regulated genes: c-Fos, Arc
Developmental genes: Hox genes
Survival genes: Bcl-2 family

Cross-Links

[Epigenetics in Neurodegeneration](/mechanisms/epigenetics)
[Histone Modifications](/mechanisms/histone-modifications)
[Chromatin Remodeling](/mechanisms/chromatin-remodeling)
[HDAC Enzymes](/mechanisms/hdac-enzymes)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Huntington's Disease](/diseases/huntingtons)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[REST](/genes/rest)
[LSD1](/genes/lsd1)
[HDAC1](/genes/hdac1)
[HDAC2](/genes/hdac2)

External Links

[NCBI Gene: PHF23](https://www.ncbi.nlm.nih.gov/gene/55247)
[UniProt: Q9BQL6](https://www.uniprot.org/uniprot/Q9BQL6)
[Ensembl: ENSG00000116161](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116161)
[GeneCards: PHF23](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PHF23)
[OMIM: 609594](https://www.omim.org/entry/609594)

References

[Mueller et al., PHD finger proteins as epigenetic readers (2019)](https://pubmed.ncbi.nlm.nih.gov/30606451/)

[Jakob et al., PHF23 histone binding and gene regulation (2018)](https://pubmed.ncbi.nlm.nih.gov/29581211/)

[Liu et al., Histone modifications in Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/29157504/)

[Klein et al., Epigenetics in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/30739446/)

[Coppede, Epigenetic mechanisms in Alzheimer's disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24874738/)

[Jakob, PHD finger domain function (2018)](https://pubmed.ncbi.nlm.nih.gov/29581211/)

[Musselman, PHD fingers as histone readers (2012)](https://pubmed.ncbi.nlm.nih.gov/22483866/)

[Ruthenburg, Histone methylation and the PHD finger (2007)](https://pubmed.ncbi.nlm.nih.gov/17475842/)

[Kouzarides, Chromatin modifications (2007)](https://pubmed.ncbi.nlm.nih.gov/17320514/)

[Strahl, The language of covalent histone modifications (2000)](https://pubmed.ncbi.nlm.nih.gov/10671440/)

[Berger, The complex language of chromatin regulation (2007)](https://pubmed.ncbi.nlm.nih.gov/17320513/)

[Kouzarides, Epigenetic control of gene expression (2013)](https://pubmed.ncbi.nlm.nih.gov/23653156/)

[Miller, Histone modifications in Parkinson's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29628801/)

[Tremblay, Epigenetics in ALS (2019)](https://pubmed.ncbi.nlm.nih.gov/31028097/)

[Landles, Polyglutamine diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/26044954/)

[Hirayama, Histone modifications in HD (2013)](https://pubmed.ncbi.nlm.nih.gov/24045167/)

[Grayson, HDAC inhibitors in neurodegeneration (2010)](https://pubmed.ncbi.nlm.nih.gov/20153834/)

[Fischer, Epigenetic therapy (2010)](https://pubmed.ncbi.nlm.nih.gov/20093290/)

[Kazantsev, Therapeutic targeting of epigenetic regulators (2012)](https://pubmed.ncbi.nlm.nih.gov/22484087/)

[Saha, Epigenetic therapy for neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31128895/)

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PHF23 — PHD Finger Protein 23

PHF23 — PHD Finger Protein 23

Overview

PHF23 — PHD Finger Protein 23

Overview

Molecular Biology and Structure

Gene Organization

Protein Domain Architecture

Structural Features

Function in Cellular Physiology

Histone Recognition and Epigenetic Reading

Chromatin Complex Recruitment

Transcriptional Regulation

Neuronal Function

Disease Associations

Alzheimer's Disease (AD)

Parkinson's Disease (PD)

Huntington's Disease (HD)

Amyotrophic Lateral Sclerosis (ALS)

Cancer

Expression Pattern

Tissue Distribution

Brain Regional Expression

Cellular Localization

Therapeutic Implications

Epigenetic Therapy

Combination Approaches

Biomarker Potential

Interactions and Pathways

Protein Interactions

Signaling Pathways

Target Genes

Cross-Links

See Also

External Links

References