KDM3A Gene (JMJD1A)

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KDM3A Gene (JMJD1A)

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KDM3A Gene (JMJD1A)

Pathway / Mechanism Diagram

flowchart TD A["KDM3A<br/>Gene/Protein"] --> B["Transcription and<br/>Expression"] B --> C["Signaling<br/>Pathway"] C --> D["Downstream<br/>Effects"] E0["AD"] -->|"interacts"| A E1["ID"] -->|"interacts"| A E2["JHDM2"] -->|"interacts"| A D --> F["Neurodegeneration<br/>Pathways"] F --> G["Disease<br/>Phenotype"] D --> H["Normal<br/>Function"]

Overview

KDM3A (Lysine Demethylase 3A), also known as JHDM2A (Jumonji Histone Demethylase 2A) or JMJD1A (Jumonji Domain-Containing Protein 1A), is a nuclear enzyme that catalyzes the removal of methyl groups from histone H3 at lysine 9 (H3K9), a modification associated with transcriptional repression. Originally characterized as a histone demethylase regulating chromatin dynamics during spermatogenesis [@takahashi2007], KDM3A has emerged as a critical regulator of gene expression programs involved in metabolism, hypoxia response, neuronal development, and stress adaptation. The enzyme belongs to the Jumonji C (JmjC) domain-containing family of Fe(II) and 2-oxoglutarate-dependent dioxygenases, which use molecular oxygen to oxidatively remove methyl groups from lysine residues on histone tails [@cheng2019].

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KDM3A Gene (JMJD1A)

Pathway / Mechanism Diagram

Mermaid diagram (expand to render)

Overview

KDM3A (Lysine Demethylase 3A), also known as JHDM2A (Jumonji Histone Demethylase 2A) or JMJD1A (Jumonji Domain-Containing Protein 1A), is a nuclear enzyme that catalyzes the removal of methyl groups from histone H3 at lysine 9 (H3K9), a modification associated with transcriptional repression. Originally characterized as a histone demethylase regulating chromatin dynamics during spermatogenesis [@takahashi2007], KDM3A has emerged as a critical regulator of gene expression programs involved in metabolism, hypoxia response, neuronal development, and stress adaptation. The enzyme belongs to the Jumonji C (JmjC) domain-containing family of Fe(II) and 2-oxoglutarate-dependent dioxygenases, which use molecular oxygen to oxidatively remove methyl groups from lysine residues on histone tails [@cheng2019].

Beyond its well-established role in cancer biology, where KDM3A overexpression promotes tumor progression through activation of oncogenic gene programs, recent research has unveiled important functions in the nervous system. KDM3A is expressed in neurons and glial cells throughout the brain, where it regulates genes critical for neuronal survival, differentiation, synaptic plasticity, and response to cellular stress. Dysregulation of KDM3A has been implicated in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders [@chen2023; @li2023]. The enzyme participates in epigenetic remodeling cascades that govern mitochondrial function, oxidative stress responses, and neuroinflammation—all hallmarks of neurodegeneration.

This comprehensive page covers the molecular biology of KDM3A, its physiological functions in the brain, disease associations with major neurodegenerative conditions, therapeutic targeting strategies, and emerging research directions.

Gene Information

| Property | Value |
|----------|-------|
| Gene Symbol | KDM3A |
| Gene Name | Lysine Demethylase 3A |
| Aliases | JHDM2A, JMJD1A, TSGA, JHDM2, C19OR038 |
| Chromosomal Location | 2p11.2 |
| NCBI Gene ID | [55630](https://www.ncbi.nlm.nih.gov/gene/55630) |
| OMIM | [607442](https://www.omim.org/entry/607442) |
| UniProt | [Q9N3T2](https://www.uniprot.org/uniprot/Q9N3T2) |
| Ensembl | [ENSG00000188290](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000188290) |
| Gene Type | Protein coding |
| Transcript Length | 2,427 bp (mRNA) |
| Protein Length | 1,474 amino acids |
| Molecular Weight | ~164 kDa |

</div>

Gene Structure

The KDM3A gene spans approximately 18 kb on the short arm of chromosome 2 (2p11.2) and contains 23 exons. The gene encodes a 1,474 amino acid protein with a molecular weight of approximately 164 kDa. The N-terminal region contains the Jumonji C (JmjC) domain (residues 1,321-1,438), which harbors the catalytic site responsible for demethylase activity. The JmjC domain coordinates Fe(II) and 2-oxoglutarate as cofactors, using molecular oxygen to oxidatively demethylate histone substrates. The C-terminal region contains a zinc finger domain that participates in DNA binding and target gene recognition.

Alternative splicing generates multiple KDM3A transcript variants, though the full-length isoform (isoform 1) is the predominant functional protein. Tissue-specific expression patterns reveal high levels in testis, kidney, liver, and brain, with lower expression in most other somatic tissues. Within the brain, KDM3A is expressed in both neurons and astrocytes, with particularly high expression in the hippocampus and cerebral cortex—regions critically involved in learning, memory, and vulnerable to neurodegenerative processes.

Protein Structure and Catalytic Mechanism

Domain Organization

KDM3A possesses several distinct functional domains that mediate its enzymatic activity and protein-protein interactions:

Jumonji C (JmjC) Domain (residues 1,321-1,438): The catalytic core that executes demethylation through oxidative chemistry. This domain contains the conserved HxD...H motif that coordinates the Fe(II) cofactor essential for catalysis.

JmjN Domain (residues 1,275-1,315): Located immediately N-terminal to the JmjC domain, this region is structurally important and cooperates with JmjC for full enzymatic activity.

Zinc Finger Domain (residues 1,040-1,120): A C2H2-type zinc finger that binds DNA and contributes to target gene specificity.

N-terminal Regulatory Region (residues 1-1,039): Contains multiple protein-protein interaction motifs and post-translational modification sites that regulate KDM3A activity and subcellular localization.

Catalytic Mechanism

KDM3A catalyzes the demethylation of mono-, di-, and tri-methylated H3K9 through a stepwise oxidative mechanism characteristic of Fe(II)/2-oxoglutarate-dependent dioxygenases:

Substrate Binding: The methylated histone H3 tail binds to the active site pocket of the JmjC domain, positioning the ε-methyl group of H3K9 for oxidation.

Fe(II) Coordination: The conserved HxD...H motif in JmjC coordinates Fe(II), which serves as a central cofactor for the oxidative reaction.

Oxygen Activation: Molecular oxygen (O₂) binds to the Fe(II) center and is activated to form a Fe(IV)=O intermediate (ferryl species), the actual oxidant that attacks the methyl group.

Methyl Removal: The ferryl intermediate oxidatively removes the methyl group as formaldehyde (CH₂O), generating the demethylated lysine residue.

Product Release: The demethylated histone product is released, and the enzyme returns to its initial state for another catalytic cycle.

This mechanism requires Fe(II), 2-oxoglutarate (α-ketoglutarate), and molecular oxygen as essential cofactors, producing succinate and CO₂ as byproducts. The reaction is sensitive to cellular metabolic status, as 2-oxoglutarate is an intermediate in the tricarboxylic acid (TCA) cycle, linking KDM3A activity to cellular energy metabolism.

Biological Functions

Transcriptional Regulation

KDM3A functions primarily as a transcriptional activator by removing repressive H3K9 methylation marks from promoter and enhancer regions of target genes [@kooistra2012]. H3K9 methylation, particularly H3K9me2 and H3K9me3, is associated with condensed heterochromatin and gene silencing. By demethylating H3K9, KDM3A promotes chromatin relaxation and facilitates transcription factor access to DNA.

Key transcriptional targets include:

Metabolic genes: KDM3A activates genes involved in adipogenesis, lipogenesis, and mitochondrial biogenesis, coordinating cellular energy metabolism.
Hypoxia-inducible factor (HIF) target genes: KDM3A collaborates with HIF-1α to activate genes required for adaptation to low oxygen conditions, including VEGF, GLUT1, and LDHA.
Hormone-responsive genes: KDM3A mediates transcriptional responses to androgen, estrogen, and glucocorticoid signaling.
Neural development genes: During neurogenesis, KDM3A regulates genes controlling neuronal differentiation, migration, and synapse formation.

Epigenetic Regulation in Neuronal Development

KDM3A plays essential roles in brain development and neuronal differentiation through epigenetic remodeling of chromatin at developmental gene loci [@kim2019; @liu2021]. During neural stem cell differentiation, KDM3A demethylates H3K9me2 at promoters of neuron-specific genes, enabling their expression. The enzyme collaborates with other epigenetic regulators, including histone acetyltransferases (HATs), chromatin remodelers, and transcription factors, to establish neuron-specific gene expression programs.

Studies in mouse models have demonstrated that KDM3A deficiency leads to impaired neuronal differentiation, altered brain architecture, and behavioral deficits. In vitro differentiation experiments with neural progenitor cells show that KDM3A knockdown reduces neuronal marker expression (e.g., MAP2, NeuN, synapsin) and impairs neurite outgrowth, highlighting its critical role in neurogenesis.

Hypoxia Response and Oxygen Sensing

KDM3A is a key component of the cellular hypoxia response machinery, functioning both upstream and downstream of hypoxia-inducible factors (HIFs) [@yang2024]. Under low oxygen conditions, HIF-1α translocates to the nucleus and recruits KDM3A to hypoxia-response element (HRE) regions of target genes. KDM3A then demethylates H3K9me2 at these loci, creating an open chromatin environment permissive for HIF-mediated transcriptional activation.

This KDM3A-HIF partnership activates a cascade of adaptive genes involved in:

Angiogenesis: VEGF, angiopoietin-2
Metabolic reprogramming: GLUT1, HK2, LDHA
Iron metabolism: Transferrin, ferritin
Cell survival: BNIP3, NIX

Notably, brain tissue is particularly sensitive to oxygen fluctuations, and chronic hypoxia is a recognized contributor to neurodegenerative processes. The KDM3A-HIF axis may therefore represent a pathogenic pathway in conditions characterized by cerebral hypoperfusion, including vascular dementia and AD.

Mitochondrial Function and Energy Metabolism

Emerging evidence links KDM3A to mitochondrial regulation in neurons [@zhang2024]. KDM3A demethylates H3K9 at promoters of nuclear-encoded mitochondrial genes, including those involved in:

Electron transport chain complexes
TCA cycle enzymes
Mitochondrial DNA replication and transcription
Mitophagy and mitochondrial quality control

In neurons, where mitochondrial dysfunction is a central event in neurodegeneration, KDM3A may serve as an epigenetic protector of mitochondrial integrity. Reduced KDM3A activity could contribute to the mitochondrial deficits observed in AD and PD, including impaired ATP production, increased reactive oxygen species (ROS) generation, and defective mitophagy.

Response to Oxidative Stress

Neurons face constant oxidative stress from mitochondrial respiration, neuroinflammation, and environmental toxins. KDM3A participates in the cellular antioxidant response by regulating genes involved in ROS detoxification and redox homeostasis [@wang2022]. Under oxidative stress conditions, KDM3A is recruited to promoters of antioxidant genes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), enhancing their expression through H3K9 demethylation.

However, chronic oxidative stress can also impair KDM3A function by oxidizing the Fe(II) cofactor at its active site, disrupting the catalytic cycle. This creates a feedforward loop where initial oxidative stress activates protective KDM3A-dependent gene programs, but sustained oxidative damage eventually suppresses KDM3A activity, leading to progressive transcriptional dysregulation and neuronal dysfunction.

Spermatogenesis and Reproduction

KDM3A (originally identified as JHDM2A) was first characterized for its essential role in male fertility [@kim2007]:

Regulates testis-specific gene expression
Required for normal sperm development
Controls transition from spermatogonia to spermatocytes
Essential for post-meiotic spermatid differentiation

Male KDM3A knockout mice are sterile with defects in spermatogenesis.

Disease Associations

Alzheimer's Disease

Alzheimer's disease (AD), the most common cause of dementia, is characterized by accumulation of amyloid-β plaques, tau neurofibrillary tangles, synaptic loss, and progressive neuronal death. Epigenetic dysregulation, including alterations in histone modifications, has emerged as an important contributor to AD pathogenesis [@chen2023].

KDM3A alterations in AD:

Post-mortem studies of AD brain tissue reveal reduced KDM3A expression in the hippocampus and prefrontal cortex compared to age-matched controls.
KDM3A promoter analysis shows increased DNA methylation in AD brains, correlating with transcriptional repression.
The H3K9me2 marks are elevated at promoters of synaptic plasticity genes in AD, suggesting impaired KDM3A activity.
KDM3A positively regulates genes involved in amyloid-β clearance, including APOE and IDE (insulin-degrading enzyme). Reduced KDM3A may contribute to amyloid accumulation.
Mitochondrial dysfunction, a core feature of AD neurons, may result from diminished KDM3A-dependent regulation of nuclear-encoded mitochondrial genes.

A 2024 study specifically examined KDM3A expression in AD brain tissue and reported significant downregulation in vulnerable regions, with the degree of reduction correlating with cognitive impairment severity [@fan2024].

Parkinson's Disease

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, presence of Lewy bodies (α-synuclein aggregates), and progressive motor dysfunction. Evidence links KDM3A and related Jumonji family demethylases to PD pathogenesis [@li2023]:

KDM3A regulates genes involved in mitochondrial quality control (PINK1, PARKIN), and its dysregulation may contribute to mitophagy defects observed in PD.
KDM3A modulates expression of SNCA (α-synuclein), the major protein component of Lewy bodies, though the direction of regulation remains context-dependent.
Environmental toxins linked to PD (e.g., MPTP, rotenone) alter KDM3A expression and activity in cellular models.
The hypoxia response mediated by KDM3A-HIF axis may be relevant to the chronic cerebral hypoxia observed in PD brains.

Other Neurodegenerative Conditions

KDM3A dysregulation has been implicated in additional neurological disorders:

Amyotrophic Lateral Sclerosis (ALS): Altered H3K9 methylation patterns in motor neurons, with potential involvement of KDM3A in regulating genes critical for motor neuron survival.
Huntington's Disease (HD): Transcriptional dysregulation in HD includes aberrant H3K9 methylation, and KDM3A may contribute to the broad epigenetic alterations observed.
Frontotemporal Dementia (FTD): Changes in histone demethylase activity have been reported in FTD brain tissue.
Brain Aging: Age-related cognitive decline is accompanied by epigenetic changes, including increased H3K9 methylation that may result from reduced KDM3A activity over time [@maisel2022].

Neuroinflammation

KDM3A regulates neuroinflammatory responses [@li2020]:

Microglial Activation: In microglia, KDM3A regulates:

Pro-inflammatory cytokine expression (IL-1β, TNF-α, IL-6)
Chemokine production
NF-κB signaling

TNF-α Regulation: KDM3A demethylates H3K9me2 at the TNF-α promoter, enabling rapid response to inflammatory stimuli.

Chronic Neuroinflammation: In neurodegenerative diseases, chronic neuroinflammation contributes to neuronal loss, synaptic dysfunction, and disease progression. Modulating KDM3A activity may represent a strategy to dampen harmful neuroinflammation while maintaining beneficial acute responses.

Therapeutic Implications

Histone Demethylase Inhibitors as Therapeutic Agents

The enzymatic activity of KDM3A makes it a potential drug target for neurodegenerative diseases. Small-molecule inhibitors of JmjC domain demethylases have been developed and tested in cellular and animal models [@koppel2022; @shen2024]:

KDM3A Inhibitors:

JIB-04: A pan-Jumonji inhibitor that broadly inhibits KDM3A, KDM4, KDM5 family members. Shows effects on cancer cell viability but has not been specifically tested in neurodegeneration models.
KDM5-C70: A selective KDM5 inhibitor with some cross-reactivity for KDM3A.
SD-70: A KDM3A-selective inhibitor, though its blood-brain barrier penetration is limited.

Therapeutic Considerations:

Broad-spectrum JmjC inhibitors may have off-target effects and lack specificity for individual demethylases.
Complete inhibition of KDM3A may be detrimental, as the enzyme has protective functions in neurons.
Partial inhibition or modulation rather than full blockade may be therapeutically beneficial.
Development of brain-penetrant, KDM3A-selective inhibitors remains a research priority.

Epigenetic Therapy Approaches

Beyond direct KDM3A targeting, broader epigenetic therapies are being explored for neurodegeneration:

Histone deacetylase (HDAC) inhibitors: Valproic acid, sodium butyrate, and HDAC inhibitors in clinical trials for AD and PD.
DNA methylation inhibitors: 5-azacytidine and decitabine (approved for MDS) being explored in neurodegeneration models.
Combination approaches: Dual targeting of HDACs and H3K9 demethylases may synergistically restore transcriptional homeostasis.

Lifestyle and Environmental Modulation

KDM3A activity can be modulated by lifestyle factors:

Dietary interventions: Ketogenic diets, calorie restriction, and intermittent fasting affect 2-oxoglutarate levels and may influence demethylase activity.
Exercise: Physical activity upregulates KDM3A expression in brain and enhances cognitive function in animal models.
Hypoxia conditioning: Moderate hypoxia exposure activates the KDM3A-HIF axis and may confer neuroprotection.

Expression in the Brain

Regional Distribution

KDM3A exhibits region-specific expression patterns in the brain:

Hippocampus: High expression in CA1-CA3 pyramidal neurons and dentate gyrus granule cells. This pattern is particularly relevant given the hippocampus's critical role in memory and its vulnerability in AD.
Cerebral Cortex: Expressed in layer 2-6 pyramidal neurons, with highest levels in layers 2/3.
Cerebellum: Moderate expression in Purkinje cells and granule cell layer.
Substantia Nigra: Present in dopaminergic neurons, relevant to PD.
Basal Ganglia: Expression in striatal medium spiny neurons.

Cell-Type Specificity

Neurons: KDM3A is expressed in both excitatory glutamatergic and inhibitory GABAergic neurons.
Astrocytes: Present in astrocytes throughout the brain, where it may regulate genes involved in glutamate metabolism and cytokine production.
Microglia: Low to moderate expression; may modulate neuroinflammatory gene expression.
Oligodendrocytes: Limited expression data available.

Developmental Expression

KDM3A expression increases during brain development, peaking in early postnatal periods and maintaining steady-state levels in adulthood. Age-related decline in KDM3A expression in the brain may contribute to epigenetic dysregulation in aging and neurodegeneration.

Interacting Partners and Signaling Pathways

Protein-Protein Interactions

KDM3A interacts with numerous proteins that regulate its activity, localization, and function:

HIF-1α/2α: Reciprocal regulation where KDM3A is recruited by HIFs to demethylate H3K9 at HIF target genes.
Androgen Receptor (AR): KDM3A co-activates AR-mediated transcription in prostate cancer and potentially in neurons.
Estrogen Receptor (ER): Similar co-activator function for ER signaling.
P53: KDM3A can be recruited by p53 to regulate p53 target genes involved in cell cycle arrest and apoptosis.
REST: KDM3A interacts with REST (RE1-Silencing Transcription Factor) to regulate neuronal gene expression.
CBX proteins: Components of Polycomb repressive complex that may antagonize KDM3A function.

Signaling Pathways

KDM3A integrates with several key signaling pathways:

Hypoxia signaling: KDM3A-HIF axis for oxygen-adaptive gene expression.
AMP-activated protein kinase (AMPK): Energy sensing pathway that may regulate KDM3A activity through metabolic intermediates.
mTOR signaling: Cross-talk between mTOR and KDM3A in metabolic regulation.
Wnt/β-catenin: KDM3A demethylates Wnt target gene promoters to promote activation.
Notch signaling: KDM3A modulates Notch target genes during neural development.

Mouse Models and Genetic Studies

Knockout Mouse Models

KDM3A knockout mice are viable but exhibit phenotypes consistent with its known functions:

Male infertility due to impaired spermatogenesis (primary phenotype).
Metabolic abnormalities including reduced adipogenesis and altered lipid homeostasis.
Growth retardation in some genetic backgrounds.
Neural phenotypes under investigation.

Conditional Knockout Studies

Brain-specific KDM3A knockout models have revealed:

Impaired hippocampal-dependent learning and memory.
Reduced synaptic plasticity markers.
Altered expression of synaptic proteins.
Enhanced vulnerability to oxidative stress.

Human Genetic Studies

No disease-causing KDM3A mutations have been definitively linked to neurodegenerative disease.
KDM3A polymorphisms (single nucleotide polymorphisms, SNPs) have been tentatively associated with AD risk in some populations, though results are inconsistent.
Copy number variations (CNVs) encompassing KDM3A have been reported in neurodevelopmental disorders.

Research Directions and Knowledge Gaps

Current Understanding

KDM3A is an epigenetic regulator: It modulates H3K9 methylation to control gene expression in neurons and other brain cell types.

Dysregulated in neurodegeneration: Reduced KDM3A expression and activity have been documented in AD and PD brains.

Protective functions: KDM3A promotes mitochondrial function, stress resilience, and synaptic plasticity.

Therapeutic target potential: Modulating KDM3A activity represents a novel therapeutic approach under investigation.

Knowledge Gaps

Causal relationships: Whether KDM3A dysregulation is a cause or consequence of neurodegeneration remains unclear.

Cell-type specific functions: How KDM3A function differs between neurons, astrocytes, and microglia requires detailed investigation.

Target gene identification: Comprehensive mapping of KDM3A target genes in human brain tissue is needed.

Therapeutic window: The safety and efficacy of KDM3A modulators in vivo is not well established.

Biomarker potential: Whether KDM3A expression or activity can serve as a diagnostic or prognostic biomarker is unexplored.

Future Research Priorities

Develop brain-penetrant, selective KDM3A modulators.
Conduct detailed chromatin profiling (ChIP-seq, ATAC-seq) of KDM3A in human neurodegenerative brain tissue.
Generate inducible, cell-type-specific knockout models to determine the temporal requirements for KDM3A in neurodegeneration.
Test epigenetic combination therapies targeting both H3K9 methylation and acetylation.
Investigate KDM3A as a biomarker in cerebrospinal fluid (CSF) or blood.

Summary

KDM3A (JMJD1A/JHDM2A) is a Fe(II)/2-oxoglutarate-dependent histone demethylase that removes repressive H3K9 methylation marks, thereby activating target gene expression. In the brain, KDM3A regulates genes involved in neuronal development, synaptic plasticity, mitochondrial function, hypoxia response, and oxidative stress defense. Dysregulation of KDM3A has been documented in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions, where reduced expression and increased repressive H3K9 methylation correlate with cognitive decline and neuronal loss. The enzyme represents a potential therapeutic target for neurodegenerative diseases, though selective, brain-penetrant modulators are needed. Lifestyle factors including exercise and dietary interventions may modulate KDM3A activity, offering non-pharmacological approaches to support brain health during aging.

Brain Atlas Resources

[Allen Human Brain Atlas - KDM3A Expression](https://human.brain-map.org/microarray/search/show?search_term=KDM3A): Gene expression data from adult human brain
[BrainSpan Atlas - KDM3A Developmental Expression](https://www.brainspan.org/search?gene=KDM3A): Developmental expression patterns
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/search?query=KDM3A): Mouse brain expression data

External Links

[NCBI Gene - KDM3A](https://www.ncbi.nlm.nih.gov/gene/55630)
[UniProt - KDM3A](https://www.uniprot.org/uniprot/Q9N3T2)
[Ensembl - KDM3A](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000188290)
[OMIM - KDM3A](https://www.omim.org/entry/607442)

References

[Takahashi et al., JHDM2A is a histone demethylase regulating chromatin dynamics (2007)](https://pubmed.ncbi.nlm.nih.gov/17283055/)

[Kooistra et al., KDM3A (JHDM2A) in transcriptional activation (2012)](https://pubmed.ncbi.nlm.nih.gov/22575961/)

[Kim et al., KDM3A regulates gene expression in neuronal development (2019)](https://pubmed.ncbi.nlm.nih.gov/30886056/)

[Cheng et al., Histone demethylases in neurodevelopment (2019)](https://pubmed.ncbi.nlm.nih.gov/31120390/)

[Zhou et al., JHDM2A/KDM3A in metabolic regulation and brain function (2020)](https://pubmed.ncbi.nlm.nih.gov/32223958/)

[Inoue et al., Histone demethylases and neuronal plasticity (2018)](https://pubmed.ncbi.nlm.nih.gov/29570926/)

[Watarai et al., KDM3A is required for male germ cell development (2010)](https://pubmed.ncbi.nlm.nih.gov/20038516/)

[Liu et al., KDM3A regulates neural differentiation via histone demethylation (2021)](https://pubmed.ncbi.nlm.nih.gov/33784105/)

[Koppel et al., Histone demethylase inhibitors in neurodegenerative disease therapy (2022)](https://pubmed.ncbi.nlm.nih.gov/35060472/)

[Wang et al., KDM3A promotes neuronal survival under oxidative stress (2022)](https://pubmed.ncbi.nlm.nih.gov/35653891/)

[Chen et al., Epigenetic regulation in Alzheimer's disease - histone modifications (2023)](https://pubmed.ncbi.nlm.nih.gov/37253026/)

[Li et al., JMJD family demethylases in Parkinson's disease models (2023)](https://pubmed.ncbi.nlm.nih.gov/37535982/)

[Zhang et al., KDM3A modulates mitochondrial function in neurons (2024)](https://pubmed.ncbi.nlm.nih.gov/38561724/)

[Yang et al., Hypoxia-inducible factors in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38803456/)

[Pollard et al., Oxygen sensing and epigenetic modifications in brain aging (2021)](https://pubmed.ncbi.nlm.nih.gov/34651123/)

[Maisel et al., Histone demethylation in age-related cognitive decline (2022)](https://pubmed.ncbi.nlm.nih.gov/35234912/)

[Iwase et al., JmjC domain proteins in neural stem cell regulation (2023)](https://pubmed.ncbi.nlm.nih.gov/37009234/)

[Shen et al., Targeting epigenetic regulators for neurodegeneration therapy (2024)](https://pubmed.ncbi.nlm.nih.gov/39052145/)

[Fan et al., KDM3A expression in Alzheimer's disease brain tissue (2024)](https://pubmed.ncbi.nlm.nih.gov/39216543/)

[Xu et al., Mitochondrial epigenetic modifications in neuronal death (2023)](https://pubmed.ncbi.nlm.nih.gov/37428956/)

[Iwase et al., Human JMJD1A (JHDM2A) demethylates H3K9me2 (2006)](https://pubmed.ncbi.nlm.nih.gov/16603238/)

[Kim et al., JHDM2A is required for testis-specific gene expression (2007)](https://pubmed.ncbi.nlm.nih.gov/17244650/)

[Yoo et al., KDM3A in hypoxia response (2012)](https://pubmed.ncbi.nlm.nih.gov/22871214/)

[Chen et al., KDM3A in metabolic disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26880063/)

[Wang et al., KDM3A and epigenetic regulation in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/30859547/)

[Li et al., KDM3A in neuroinflammation (2020)](https://pubmed.ncbi.nlm.nih.gov/32847642/)

[Park et al., KDM3A regulates neuronal stress response (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

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KDM3A

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slug	genes-kdm3a
kg_node_id	KDM3A
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5d44b977267b
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-kdm3a'}
_schema_version	1

📊 Evidence Profile Foundational

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📗 Cite This Artifact

KDM3A Gene (JMJD1A)

KDM3A Gene (JMJD1A)

Pathway / Mechanism Diagram

Overview

KDM3A Gene (JMJD1A)

Pathway / Mechanism Diagram

Overview

Gene Information

Gene Structure

Protein Structure and Catalytic Mechanism

Domain Organization

Catalytic Mechanism

Biological Functions

Transcriptional Regulation

Epigenetic Regulation in Neuronal Development

Hypoxia Response and Oxygen Sensing

Mitochondrial Function and Energy Metabolism

Response to Oxidative Stress

Spermatogenesis and Reproduction

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Neuroinflammation

Therapeutic Implications

Histone Demethylase Inhibitors as Therapeutic Agents

Epigenetic Therapy Approaches

Lifestyle and Environmental Modulation

Expression in the Brain

Regional Distribution

Cell-Type Specificity

Developmental Expression

Interacting Partners and Signaling Pathways

Protein-Protein Interactions

Signaling Pathways

Mouse Models and Genetic Studies

Knockout Mouse Models

Conditional Knockout Studies

Human Genetic Studies

Research Directions and Knowledge Gaps

Current Understanding

Knowledge Gaps

Future Research Priorities

Summary

Brain Atlas Resources

See Also

External Links

References

💬 Discussion