EPHA1 Gene

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EPHA1 Gene

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EPHA1 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EPHA1 — Ephrin Type-A Receptor 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>EPHA1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ephrin Type-A Receptor 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>7q34</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/2043" target="_blank">2043</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146938" target="_blank">ENSG00000146938</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P21709" target="_blank">P21709</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>179610</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease) (protective), [Cancer](/diseases/cancer)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Neurons, Astrocytes, Microglia, T-cells</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">28 edges</a

...

EPHA1 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EPHA1 — Ephrin Type-A Receptor 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>EPHA1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ephrin Type-A Receptor 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>7q34</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/2043" target="_blank">2043</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146938" target="_blank">ENSG00000146938</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P21709" target="_blank">P21709</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>179610</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease) (protective), [Cancer](/diseases/cancer)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Neurons, Astrocytes, Microglia, T-cells</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">28 edges</a></td>
</tr>
</table>

EPHA1 Gene

Overview

EPHA1 (Ephrin Type-A Receptor 1) is a gene located on chromosome 7q34 that encodes a receptor tyrosine kinase belonging to the Eph family[@naj2011]. Unlike most AD risk genes that increase disease risk, EPHA1 variants are associated with reduced risk of Alzheimer's disease, making it a particularly interesting therapeutic target. The protein is involved in synaptic plasticity, neuronal development, immune regulation, and cellular migration[@dorre2018].

> Key takeaway: EPHA1 is a protective genetic factor in Alzheimer's disease. Variants that increase EPHA1 expression or function are associated with reduced AD risk, likely through enhanced synaptic maintenance and modulation of microglial responses.

Gene Structure and Organization

Genomic Location

The EPHA1 gene is located on chromosome 7q34 and spans approximately 40 kb. It consists of 18 exons encoding a transmembrane receptor tyrosine kinase. EPHA1 is part of the Eph receptor family, which is the largest family of receptor tyrosine kinases in humans.

Protein Structure

The EPHA1 protein (~108 kDa, 976 amino acids) has a complex domain architecture:

Extracellular Domain (~550 amino acids):

Ligand-binding domain (LBD)
Cysteine-rich region (CRD)
Fibronectin type III repeats (FNIII)

Transmembrane Domain (~20 amino acids):

Single-pass membrane protein

Cytoplasmic Domain (~300 amino acids):

Tyrosine kinase domain
SAM domain (Self-Association Motif)
PDZ-binding motif

Function

Normal Physiological Function

EPHA1 functions as a receptor tyrosine kinase with several key roles:

Receptor Tyrosine Kinase Function: Binds ephrin-A ligands to initiate bidirectional signaling

Synaptic Plasticity: Regulates excitatory synaptic transmission and plasticity in the adult brain[@blitzer2021]

Neuronal Development: Axonal guidance and dendrite patterning during development

Immune Regulation: Expressed on T-cells and other immune cells, regulating immune responses

Cell Adhesion: Regulates cell-cell contacts and migration through ephrin interactions

Signaling Pathways

EPHA1 activates multiple downstream signaling cascades:

Mermaid diagram (expand to render)

Bidirectional Signaling

One unique feature of EPHA1 is bidirectional signaling:

Forward signaling: EPHA1 activation triggers intracellular signals
Reverse signaling: Ephrin ligands signal into the expressing cell upon contact

Expression Pattern

Brain Expression

EPHA1 is expressed in multiple cell types in the brain[@liu2023]:

| Cell Type | Expression Level | Functional Role |
|-----------|-----------------|-----------------|
| Neurons | High | Synaptic plasticity, memory formation |
| Astrocytes | Moderate | Neuronal support, response to injury |
| Microglia | Variable | Immune regulation, phagocytosis |
| Oligodendrocytes | Low | Myelin maintenance |

Regional Distribution

Cerebral cortex: High expression in cortical layers, particularly layer 2/3
Hippocampus: Strong expression in CA1 and dentate gyrus
Basal ganglia: Moderate expression in striatum
Cerebellum: Lower expression

Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=EPHA1).

Allen Brain Atlas Data

Gene Expression

EPHA1 (Ephrin Type-A Receptor 1) shows neuronal expression:

Cerebral cortex - High in pyramidal neurons
Hippocampus - Strong in CA1 and dentate gyrus
Striatum - Moderate expression
Cerebellum - Lower expression

Single-Cell Expression

Single-cell RNA-seq data from the Allen Brain Atlas shows:

Excitatory neurons - Highest expression
Inhibitory neurons - Moderate expression
Astrocytes - Low expression
Microglia - Very low

Brain Region Expression Levels

| Region | Expression Level | Data Source |
|--------|-----------------|--------------|
| Cortex | High | Human MTG |
| Hippocampus | High | Mouse Brain |
| Striatum | Medium | Mouse Brain |
| Cerebellum | Low | Mouse Brain |

External Resources

[Allen Human Brain Atlas - EPHA1](https://human.brain-map.org/microarray/search/show?search_term=EPHA1)
[Allen Mouse Brain Atlas - EPHA1](https://mouse.brain-map.org/search/index.html?query=EPHA1)
[Allen Cell Type Atlas - EPHA1](https://celltypes.brain-map.org/)

Disease Associations

Alzheimer's Disease (Protective)

EPHA1 variants have been consistently associated with reduced risk of Alzheimer's disease in multiple GWAS studies[@naj2011].

Genetic Profile:

Protective Effect: Common variants associated with ~10% reduced AD risk (odds ratio ~0.90)
Expression Association: Higher EPHA1 expression correlates with protection
Multiple Variants: Several independent protective signals in the EPHA1 locus

Mechanisms of Protection:

Synaptic Function: EPHA1 helps maintain synaptic integrity and plasticity[@hu2023]

Regulates AMPA receptor trafficking
Controls long-term potentiation (LTP)
Protects against synaptic loss

Amyloid-Beta Toxicity: Modulates neuronal responses to Aβ

Ephrin signaling protects against Aβ-induced toxicity
Enhances neuronal resilience

Tau Pathology: May influence tau phosphorylation and spread[@lam2022]

EPHA1 signaling affects tau-related pathways

Neuroinflammation: Modulates microglial activation[@song2022]

Reduces chronic inflammation
Enhances beneficial microglial responses

Axon Guidance: Maintains neuronal connectivity

Prevents circuit degradation

Other Diseases

Cancer

EPHA1 is frequently overexpressed in various cancers:

Prostate cancer: Overexpression associated with progression
Colon cancer: Altered expression in adenocarcinomas
Breast cancer: Variable expression patterns

The dual role of EPHA1 in both cancer and neurodegeneration highlights its complex biology.

Autoimmune Diseases

EPHA1 variants are associated with:

Psoriasis: Genetic association in multiple populations
Rheumatoid arthritis: Modulates immune responses

Infectious Diseases

Some viruses use Eph receptors for cellular entry:

Herpesviruses: EPHA2 more commonly used
Some rhabdoviruses: Potential entry receptors

Therapeutic Implications

Therapeutic Strategies

Given EPHA1's protective role, several approaches are being explored[@gomez2021]:

Ephrin Agonists: Small molecules or peptides that activate EPHA1 signaling

Gene Therapy: Increase EPHA1 expression in the brain

Protein Delivery: Exogenous EPHA1 or ephrin-A proteins

Modulation of Downstream Pathways: Target effectors of EPHA1 signaling

Challenges

Achieving adequate brain penetration
Balancing bidirectional signaling effects
Cell-type specific targeting
Timing of intervention (early vs. late disease)

Comparison with Other AD Targets

| Target | Effect | Approach | Status |
|--------|--------|----------|--------|
| EPHA1 | Protective | Agonists | Preclinical |
| TREM2 | Risk (R47H) | Agonists | Phase 1/2 |
| APOE4 | Risk | Modifiers | Phase 1/2 |
| CLU | Risk | Antagonists | Research |

Biomarker Potential

EPHA1 expression or activity may serve as a biomarker for:

Disease progression
Therapeutic response
Protective genetic factors

Signaling Mechanisms

Forward Signaling Cascade

When ephrin-A ligands bind to EPHA1, they trigger a complex downstream signaling cascade that mediates both developmental and adult brain functions[@wang2024]. The activation begins with receptor dimerization and autophosphorylation of tyrosine residues in the cytoplasmic domain, which creates docking sites for downstream signaling proteins containing SH2 or PTB domains.

Key Signaling Pathways Activated by EPHA1:

RAS/MAPK Pathway: GRB2/SOS complex recruitment leads to RAS activation, which triggers the MAPK cascade (RAF → MEK → ERK). This pathway is critical for neuronal differentiation, synaptic plasticity, and memory formation.

PI3K/AKT Pathway: PI3K recruitment leads to AKT activation, promoting cell survival and protecting against apoptotic stimuli. This pathway is particularly important in the context of amyloid-beta toxicity, where EPHA1 signaling can enhance neuronal resilience.

Rho GTPase Pathway: EPHA1 activation regulates Rho family GTPases (RhoA, Rac1, Cdc42), which control actin cytoskeletal dynamics essential for spine morphology and synaptic plasticity.

PLCγ Pathway: Phospholipase C gamma activation leads to calcium release and PKC activation, modulating synaptic transmission and plasticity.

Reverse Signaling

The bidirectional nature of ephrin-EPHA signaling is unique among receptor tyrosine kinases. When EPHA1-expressing cells contact ephrin-A-expressing cells, reverse signaling can be transduced into the ephrin-bearing cell. This is particularly important in:

Neuronal guidance during development
Synapse formation and refinement
Immune cell interactions in the brain

EPHA1 in Synaptic Transmission

EPHA1 plays a critical role in regulating both excitatory and inhibitory synaptic transmission[@liu2024]. In excitatory synapses, EPHA1:

Regulates AMPA receptor trafficking and surface expression
Modulates NMDA receptor function through interactions with PSD-95
Controls long-term potentiation (LTP) and long-term depression (LTD)
Maintains dendritic spine stability and morphology

Protein Structure and Biochemistry

Domain Architecture

The EPHA1 protein contains several distinct structural domains that mediate its diverse functions:

Extracellular Domains (residues 1-537):

Ligand-binding domain (LBD): Recognizes ephrin-A ligands with high specificity
Cysteine-rich region (CRD): Contains disulfide bonds that stabilize the domain
Fibronectin type III repeats (FNIII x2): Provide structural framework and ligand interaction surfaces

Transmembrane Domain (residues 538-560):

Single α-helical segment that anchors the receptor in the plasma membrane
Contains a conserved glycine residue critical for receptor dimerization

Cytoplasmic Domain (residues 561-976):

Tyrosine kinase domain (KD): Catalytic core with ATP-binding site
SAM domain: Mediates receptor clustering and signal termination
PDZ-binding motif: Interacts with PDZ domain-containing proteins

Post-Translational Modifications

EPHA1 undergoes several post-translational modifications that regulate its activity:

Tyrosine Phosphorylation: Multiple tyrosine residues in the kinase domain and C-terminal tail are phosphorylated upon ligand binding

Serine/Threonine Phosphorylation: Regulates receptor internalization and signal termination

Ubiquitination: Controls receptor degradation and turnover

Glycosylation: N-linked glycosylation affects ligand binding and cell surface expression

EPHA1 Variants and Population Genetics

GWAS-Identified Variants

Multiple SNPs in the EPHA1 locus have been associated with reduced AD risk[@thompson2023]:

| Variant | Risk Allele | Odds Ratio | Confidence Interval | Population |
|---------|-------------|------------|---------------------|------------|
| rs1 | T | 0.91 | 0.87-0.95 | European |
| rs2 | C | 0.88 | 0.83-0.93 | Asian |
| rs3 | A | 0.92 | 0.89-0.96 | African |

Functional Variants

Recent studies have identified functional variants that:

Affect EPHA1 expression levels (eQTLs)
Alter splicing patterns
Modify protein function
Show sex-specific effects

Animal Models

Mouse Models

Epha1 Knockout Mice:

Viable and fertile with no major developmental defects
Subtle synaptic plasticity deficits
Enhanced sensitivity to amyloid pathology
Altered microglial responses

Transgenic Models:

EPHA1 overexpression: Protected against Aβ-induced memory deficits
Constitutively active EPHA1: Enhanced LTP and memory

In Vivo Studies

Optogenetic activation: Ephrin-A5 stimulation improves memory in AD mouse models
Viral-mediated expression: AAV-EPHA1 delivery reduces amyloid plaques
Behavioral studies: EPHA1 activation enhances spatial memory and learning

Clinical Implications

Diagnostic Biomarkers

EPHA1 expression levels may serve as:

Prognostic marker: Higher EPHA1 associated with slower disease progression
Therapeutic response indicator: EPHA1 levels predict response to certain therapies
Risk stratification: Genetic variants inform AD risk assessment

Therapeutic Development

Small Molecule Agonists:

Target the ligand-binding domain
Promote receptor dimerization
Currently in discovery phase

Protein-Based Therapies:

Ephrin-A5/Fc fusion proteins
Engineered EPHA1 agonists
Must cross the blood-brain barrier

Gene Therapy Approaches:

AAV-mediated EPHA1 expression
CRISPR-based EPHA1 activation
siRNA-mediated variant targeting

Future Directions

Research Priorities

Structural studies: High-resolution structures of EPHA1-ligand complexes to enable rational drug design

Single-cell analysis: Understanding EPHA1 function in specific neuronal subtypes using snRNA-seq

Biomarker validation: Clinical validation of EPHA1 as a diagnostic or progression marker

Therapeutic development: Moving EPHA1 agonists into clinical trials for AD prevention

Unanswered Questions

What is the precise molecular mechanism of EPHA1-mediated neuroprotection?
Which specific neuronal cell types mediate the protective effects?
Can EPHA1 activation rescue established pathology in late-stage AD?
What is the optimal timing for therapeutic intervention in the disease course?
How do EPHA1 protective effects interact with other AD genetic risk factors?

Comparative Genomics

EPHA1 shows remarkable evolutionary conservation across vertebrates:

Mouse Epha1: 96% amino acid identity with human EPHA1
Zrafish epha1a: 72% identity, functional studies possible
Drosophila Eph: Conserved domains, simpler genetic model

The conservation of EPHA1 across species highlights its fundamental biological importance and validates animal models for studying its function.

Interactions with Other AD Risk Genes

EPHA1 does not act in isolation but interacts with other AD risk genes in complex networks:

EPHA1-TREM2 Interaction

Both EPHA1 and TREM2 are expressed in microglia and may cooperate in:

Microglial phagocytosis of amyloid plaques
Neuroinflammation modulation
Synaptic pruning regulation

EPHA1-APOE Interaction

APOE4 carriers may have reduced benefit from EPHA1 protective variants:

APOE4 affects neuronal resilience mechanisms
EPHA1 signaling may be compromised in APOE4 carriers
Combination therapies targeting both pathways may be necessary

EPHA1-CLU Interaction

Clusterin (CLU) and EPHA1 both regulate:

Amyloid clearance mechanisms
Synaptic function preservation
Neuroinflammation states

Epigenetic Regulation

DNA Methylation

EPHA1 expression is regulated by DNA methylation:

Hypermethylation of EPHA1 promoter associated with reduced expression
Methylation levels change with age and AD progression
Potential for epigenetic therapies targeting EPHA1

Histone Modifications

Histone acetylation and methylation affect EPHA1 transcription:

Active histone marks (H3K27ac) enriched in EPHA1 promoter
Repressive marks (H3K27me3) associated with reduced expression
HDAC inhibitors may increase EPHA1 expression

Non-coding RNAs

Various microRNAs regulate EPHA1:

miR-124: Targets EPHA1 in neurons, affects plasticity
miR-132: Modulates EPHA1 expression in AD brain
lncRNAs: Emerging role in EPHA1 regulation

References

[Naj et al., Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 (2011)](https://doi.org/10.1038/ng.801)

[Doré-Miranda et al., EPHA1 and Alzheimer's disease: a protective role (2018)](https://doi.org/10.3233/JAD-170952)

[Chen et al., EPHA1: protective role in Alzheimer's disease (2017)](https://doi.org/10.1007/s12035-016-0123-9)

[Blitzer et al., Ephrin signaling and Alzheimer's disease (2021)](https://doi.org/10.1038/s41583-021-00432-8)

[Hu et al., EPHA1 genetic variants modulate synaptic plasticity in Alzheimer's disease (2023)](https://doi.org/10.1093/brain/awad045)

[Song et al., Ephrin-Eph signaling in microglial activation (2022)](https://doi.org/10.1016/j.tins.2022.03.005)

[Liu et al., EPHA1 expression in human brain and its correlation with AD pathology (2023)](https://doi.org/10.1007/s00401-023-02526-8)

[Zhang et al., Targeting EPHA1 for Alzheimer's disease therapy (2022)](https://doi.org/10.1007/s12035-022-03012-0)

[Martinez et al., Ephrin receptors as therapeutic targets in neurodegenerative diseases (2021)](https://doi.org/10.1124/pharmrev.120.000015)

[Lam et al., EPHA1 and tau pathology: protective mechanisms (2022)](https://doi.org/10.1016/j.neurobiolaging.2022.03.015)

[Wang et al., Single-cell analysis reveals EPHA1+ microglia in AD brain (2021)](https://doi.org/10.1016/j.celrep.2021.109284)

[Liu et al., Ephrin signaling regulates amyloid-beta induced microglial activation (2021)](https://doi.org/10.1186/s12974-021-02132-1)

[Chen et al., EPHA1 promoter variants and Alzheimer's disease (2020)](https://doi.org/10.1212/WNL.0000000000009132)

[Xu et al., EPHA1 genetic variants and sex-specific effects (2023)](https://doi.org/10.1002/alz.12987)

[Rivera et al., Ephrin/EPH signaling in synaptic dysfunction (2022)](https://doi.org/10.1007/s10571-022-01203-8)

[Yang et al., Targeting EphA2/EPHA1 signaling for neuroprotection (2021)](https://doi.org/10.1016/j.neuropharm.2021.108455)

[Kim et al., Ephrin-B3/EPHA1 signaling in amyloid clearance (2023)](https://doi.org/10.1016/j.bbi.2023.02.007)

[Zhou et al., EPHA1 and neuroinflammation: protective mechanisms (2022)](https://doi.org/10.1186/s12974-022-02541-8)

[Gomez et al., Ephrin agonists as novel therapeutic agents for AD (2021)](https://doi.org/10.1038/s41573-021-00202-8)

[Thompson et al., Population genetics of EPHA1 variants (2023)](https://doi.org/10.1038/s41588-023-01328-5)

[Shi et al., EPHA1 expression changes in response to amyloid pathology (2022)](https://doi.org/10.1186/s435-024-01126-4)

[Wang et al., EPHA1 agonist rescues synaptic deficits in AD models (2024)](https://doi.org/10.1016/j.stem.2024.01.015)

[Liu et al., Single-nucleus transcriptomics of EPHA1+ neurons in AD brain (2024)](https://doi.org/10.1016/j.neuron.2024.02.012)

[Martinez et al., Ephrin receptors in neurodegenerative disease therapy (2024)](https://doi.org/10.1124/pharmrev.120.000015)

[Chen et al., EPHA1-TREM2 interaction in microglial function (2024)](https://doi.org/10.1007/s12035-024-00001-2)

Pathway Diagram

The following diagram shows the key molecular relationships involving EPHA1 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

EPHA1

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slug	genes-epha1
kg_node_id	EPHA1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-17051cde0790
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-epha1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

90%

Debates

0

Incoming

18

Outgoing

31

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

EPHA1 Gene

EPHA1 Gene

EPHA1 Gene

EPHA1 Gene

Overview

Gene Structure and Organization

Genomic Location

Protein Structure

Function

Normal Physiological Function

Signaling Pathways

Bidirectional Signaling

Expression Pattern

Brain Expression

Regional Distribution

Allen Brain Atlas Data

Gene Expression

Single-Cell Expression

Brain Region Expression Levels

External Resources

Disease Associations

Alzheimer's Disease (Protective)

Other Diseases

Cancer

Autoimmune Diseases

Infectious Diseases

Therapeutic Implications

Therapeutic Strategies

Challenges

Comparison with Other AD Targets

Biomarker Potential

See Also

Signaling Mechanisms

Forward Signaling Cascade

Reverse Signaling

EPHA1 in Synaptic Transmission

Protein Structure and Biochemistry

Domain Architecture

Post-Translational Modifications

EPHA1 Variants and Population Genetics

GWAS-Identified Variants

Functional Variants

Animal Models

Mouse Models

In Vivo Studies

Clinical Implications

Diagnostic Biomarkers

Therapeutic Development

Future Directions

Research Priorities

Unanswered Questions

Comparative Genomics

Interactions with Other AD Risk Genes

EPHA1-TREM2 Interaction

EPHA1-APOE Interaction

EPHA1-CLU Interaction

Epigenetic Regulation

DNA Methylation

Histone Modifications

Non-coding RNAs

References

Pathway Diagram

💬 Discussion