KDM2A Gene

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KDM2A Gene

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title: KDM2A Gene

KDM2A Gene

Overview

KDM2A (Lysine Demethylase 2A), also known as FBXL11 or JHDM1A (Jumonji Domain-Containing Histone Demethylase 1A), is a histone demethylase that specifically removes methyl groups from histone H3 at lysine 36 (H3K36). This enzyme plays critical roles in regulating transcription, DNA repair, cellular differentiation, and has emerged as a significant player in neurodegenerative disease pathogenesis. KDM2A belongs to the JmjC domain-containing family of histone demethylases, which are Fe(II) and 2-oxoglutarate-dependent oxygenases that catalyze the oxidative removal of methyl groups from lysine residues on histone tails. [@tsukada2006, @kooistra2012]

Gene Information

| Property | Value |
|----------|-------|
| Gene Symbol | KDM2A |
| Gene Name | Lysine Demethylase 2A |
| Aliases | FBXL11, JHDM1A, NEDMCL, CXXC8 |
| Chromosomal Location | 11q13.1 |
| NCBI Gene ID | [22992](https://www.ncbi.nlm.nih.gov/gene/22992) |
| OMIM | [605469](https://www.omim.org/entry/605469) |
| UniProt | [Q9Y2K2](https://www.uniprot.org/uniprot/Q9Y2K2) |
| Ensembl | [ENSG00000107140](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000107140) |
| Protein Class | Fe(II)/2-oxoglutarate-dependent dioxygenase |
| Expression | Ubiquitous, highest in brain and testis |

</div>

Protein Structure and Function

Catalytic Mechanism

...

title: KDM2A Gene

KDM2A Gene

Overview

KDM2A (Lysine Demethylase 2A), also known as FBXL11 or JHDM1A (Jumonji Domain-Containing Histone Demethylase 1A), is a histone demethylase that specifically removes methyl groups from histone H3 at lysine 36 (H3K36). This enzyme plays critical roles in regulating transcription, DNA repair, cellular differentiation, and has emerged as a significant player in neurodegenerative disease pathogenesis. KDM2A belongs to the JmjC domain-containing family of histone demethylases, which are Fe(II) and 2-oxoglutarate-dependent oxygenases that catalyze the oxidative removal of methyl groups from lysine residues on histone tails. [@tsukada2006, @kooistra2012]

Gene Information

| Property | Value |
|----------|-------|
| Gene Symbol | KDM2A |
| Gene Name | Lysine Demethylase 2A |
| Aliases | FBXL11, JHDM1A, NEDMCL, CXXC8 |
| Chromosomal Location | 11q13.1 |
| NCBI Gene ID | [22992](https://www.ncbi.nlm.nih.gov/gene/22992) |
| OMIM | [605469](https://www.omim.org/entry/605469) |
| UniProt | [Q9Y2K2](https://www.uniprot.org/uniprot/Q9Y2K2) |
| Ensembl | [ENSG00000107140](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000107140) |
| Protein Class | Fe(II)/2-oxoglutarate-dependent dioxygenase |
| Expression | Ubiquitous, highest in brain and testis |

</div>

Protein Structure and Function

Catalytic Mechanism

KDM2A catalyzes the demethylation of histone lysine residues through a hydroxylation-based mechanism requiring:

Fe(II) ion as a cofactor in the active site
2-oxoglutarate (2-OG) as a co-substrate
Molecular oxygen as the oxidant

The reaction proceeds via formation of a reactive ferryl intermediate that attacks the methyl group, resulting in formaldehyde release and demethylation of the lysine residue. [@tsukada2006]

Substrate Specificity

KDM2A demonstrates the following substrate specificity:

Primary substrate: H3K36me2 (dimethylated lysine 36 on histone H3)
Secondary substrates: H3K36me1, H3K36me0
Weak activity: H3K4me3 (trimethylated lysine 4)

The preference for H3K36me2 distinguishes KDM2A from other histone demethylases, as many JmjC domain proteins target H3K4, H3K9, or H3K27 instead. [@cheng2009]

Domain Architecture

KDM2A contains several functional domains:

JmjC Domain (residues 400-750): The catalytic domain containing the HxD motif required for Fe(II) binding and the HxH motif for 2-OG binding. This domain mediates the actual demethylase activity.

CXXC Domain (residues 1-100): A zinc-finger DNA-binding domain that targets KDM2A to CpG-rich promoter regions. This domain recognizes unmethylated CpG islands and recruits the demethylase complex to specific genomic loci. [@frohwitter2014]

F-box Domain (residues 250-300): Mediates interactions with SKP proteins and assembles into the SCF (SKP1-CUL1-F-box) ubiquitin ligase complex, enabling both demethylase activity and potential ubiquitination functions. [@klose2007]

LRR Domain (residues 150-250): Leucine-rich repeat region involved in protein-protein interactions and substrate recognition.

Protein-Protein Interactions

KDM2A functions as part of larger protein complexes:

NuRD Complex: Associates with the nucleosome remodeling and deacetylase (NuRD) complex to coordinate chromatin remodeling and transcriptional repression
SCF Complex: Incorporates into SCF E3 ubiquitin ligase complexes for protein turnover
Polycomb Proteins: Interacts with PRC2 components for gene silencing
Transcription Factors: Binds to various transcription factors including NF-κB, p53, and REST to modulate target gene expression [@black2012]

Physiological Roles

Transcriptional Regulation

KDM2A plays a complex role in transcription through histone demethylation:

Repressive Function: By removing H3K36me2 (a mark associated with active transcription), KDM2A promotes transcriptional repression. This is particularly important at:

Promoter regions of actively transcribed genes
Gene bodies where H3K36me2 marks exon-intron boundaries
Enhancer elements controlling cell-type specific gene expression

Gene-Specific Activation: In some contexts, KDM2A can actually activate transcription by:

Removing repressive H3K36me2 from specific promoters
Facilitating the binding of transcription activators
Competing with other demethylases that target H3K4me3 [@walport2014]

DNA Damage Response

KDM2A is recruited to DNA damage sites and regulates the repair of various types of DNA damage:

Nucleotide Excision Repair (NER): KDM2A demethylates H3K36me2 at DNA damage sites, allowing recruitment of repair factors like XPA and XPG. This facilitates the removal of bulky DNA adducts and helix-distorting lesions.

Base Excision Repair (BER): KDM2A modulates chromatin accessibility at sites of oxidative DNA damage, affecting the recruitment of DNA glycosylases and downstream repair components.

DNA Damage Checkpoint: KDM2A regulates the expression of cell cycle checkpoint genes through histone modifications, ensuring proper cell cycle arrest in response to DNA damage. [@nottke2009]

Cell Cycle Regulation

KDM2A controls cell proliferation through multiple mechanisms:

G1/S Transition: KDM2A represses cyclin-dependent kinase inhibitors and promotes the expression of S-phase entry genes, facilitating the G1 to S transition.

Cell Cycle Exit: During differentiation, KDM2A promotes cell cycle exit by repressifying proliferation genes and allowing the establishment of differentiation-specific chromatin states.

Senescence: KDM2A is upregulated during cellular senescence and contributes to the senescence-associated secretory phenotype (SASP) through epigenetic regulation of inflammatory genes. [@janzer2012]

Neural Development and Function

Emerging evidence highlights critical roles for KDM2A in the nervous system:

Neural Stem Cell Maintenance: KDM2A regulates the balance between neural stem cell self-renewal and differentiation. Loss of KDM2A in neural progenitor cells leads to premature differentiation and depletion of the stem cell pool. [@wang2013]

Neuronal Differentiation: During cortical development, KDM2A is dynamically expressed and controls the timing of neuronal differentiation through epigenetic regulation of Notch signaling pathway genes and other key developmental regulators. [@cho2015]

Synaptic Plasticity: KDM2A is expressed in post-mitotic neurons and may regulate synaptic plasticity-related gene expression, though this remains an area of active investigation.

Expression Pattern

KDM2A exhibits tissue-specific expression:

Highest expression: Brain (cerebral cortex, hippocampus, cerebellum), testis
Moderate expression: Heart, skeletal muscle, kidney, liver
Low expression: Most other tissues

Within the brain, KDM2A is expressed in:

Neurons (particularly in the hippocampus and cortical layers)
Glial cells (astrocytes, oligodendrocytes)
Neural stem cells in the subventricular zone and dentate gyrus

Disease Associations

Alzheimer's Disease

KDM2A has emerged as a significant player in Alzheimer's disease pathogenesis through multiple mechanisms:

Amyloid Metabolism: Studies have shown that KDM2A regulates amyloid precursor protein (APP) processing and amyloid-beta (Aβ) production. KDM2A deficiency leads to increased Aβ generation through alterations in γ-secretase component expression and altered chromatin states at APP-processing genes. [@chen2022]

Tau Pathology: KDM2A regulates tau phosphorylation and aggregation through modulation of kinase and phosphatase expression. In AD models, KDM2A dysregulation contributes to hyperphosphorylated tau accumulation and neurofibrillary tangle formation. [@park2020]

Neuroinflammation: KDM2A modulates neuroinflammatory responses in AD by regulating the expression of cytokines and inflammatory mediators. Loss of KDM2A in microglia leads to heightened inflammatory responses and increased neurotoxicity. [@fan2017]

Epigenetic Dysregulation: Global histone methylation changes are observed in AD brain, with altered H3K36me2 patterns correlating with disease progression. This suggests broader epigenetic dysfunction involving KDM2A and related enzymes. [@zhang2016]

Parkinson's Disease

KDM2A is implicated in Parkinson's disease through several mechanisms:

α-Synuclein Regulation: KDM2A may regulate the expression of SNCA (the gene encoding α-synuclein) through epigenetic mechanisms. Altered KDM2A activity could contribute to α-synuclein aggregation in PD. [@zhao2018]

Mitochondrial Function: KDM2A regulates genes involved in mitochondrial dynamics and function. In PD models, KDM2A dysregulation contributes to mitochondrial dysfunction, a hallmark of dopaminergic neuron degeneration.

Oxidative Stress: KDM2A responds to oxidative stress by regulating antioxidant gene expression. Impaired KDM2A function may exacerbate oxidative damage in PD pathogenesis.

Neuroinflammation: Similar to AD, KDM2A modulates microglial activation and neuroinflammatory responses in PD models.

Other Neurodegenerative Disorders

Amyotrophic Lateral Sclerosis (ALS): KDM2A expression is altered in ALS models and patient tissue, with implications for motor neuron survival and protein homeostasis.

Huntington's Disease: KDM2A may regulate mutant huntingtin expression and function, though this requires further investigation.

Aging-Related Neurodegeneration: KDM2A is considered a "gerontogene" - its expression and activity change with age, contributing to age-related cognitive decline and increased susceptibility to neurodegenerative diseases. [@khan2019]

Therapeutic Implications

Small Molecule Inhibitors

Several KDM2A inhibitors have been developed and tested in preclinical models:

KDOAM-25: A potent KDM2A/2B inhibitor that shows neuroprotective effects in cellular models of neurodegeneration
PKF118-310: Originally identified as a KDM2A inhibitor, shows effects on cancer cell proliferation
Natural compounds: Certain flavonoids and polyphenols show inhibitory activity against KDM2A

Therapeutic Strategies

Several approaches are being explored:

Enzyme Activation: Developing small molecules that enhance KDM2A activity to restore proper histone methylation patterns

Targeted Delivery: Nanoparticle-based delivery of KDM2A-targeting agents to the brain

Epigenetic Combination Therapy: Combining KDM2A modulators with other epigenetic drugs (HDAC inhibitors, DNMT inhibitors)

Gene Therapy: Viral vector-mediated delivery of KDM2A or KDM2A-related genes [@liu2021]

Challenges and Future Directions

Blood-brain barrier penetration: Most KDM2A modulators have limited CNS penetration
Selectivity: Achieving selectivity for KDM2A over related demethylases is challenging
Biomarkers: Need for biomarkers to monitor target engagement and therapeutic response
Combination approaches: Rational design of combination therapies for synergistic effects

Summary

KDM2A is a Fe(II)/2-oxoglutarate-dependent histone demethylase with substrate specificity for H3K36me2. Through its catalytic activity and protein-protein interactions, KDM2A regulates transcription, DNA repair, cell cycle progression, and neural development. Growing evidence implicates KDM2A dysregulation in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, making it a promising therapeutic target. Understanding the precise mechanisms by which KDM2A contributes to neurodegeneration will be critical for developing effective neuroprotective strategies. [@wang2023]

External Links

[NCBI Gene - KDM2A](https://www.ncbi.nlm.nih.gov/gene/22992)
[UniProt - KDM2A](https://www.uniprot.org/uniprot/Q9Y2K2)
[Ensembl - KDM2A](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000107140)
[HGNC - KDM2A](https://www.genenames.org/data/hgnc_data.php?hgnc_id=25558)

Brain Atlas Resources

Allen Brain Atlas

[Allen Human Brain Atlas](https://human.brain-map.org/): Gene expression data across brain regions
[Allen Cell Type Atlas](https://celltype.brain-map.org/): Cell type-specific expression data
[BrainSpan Atlas](https://brainspan.org/): Developmental transcriptome data

Other Resources

[GTEx Portal](https://gtexportal.org/): Tissue expression atlas
[UCSC Genome Browser](https://genome.ucsc.edu/): Genomic context and epigenetic marks

References

[Tsuruki et al., Histone demethylase JHDM1 family in transcription regulation (2005)](https://doi.org/10.1074/jbc.M501361200)

[Tsukada et al., Nature (2006)](https://doi.org/10.1038/nature04629)

[Kooistra & Helin, Nature Reviews Molecular Cell Biology (2012)](https://doi.org/10.1038/nrm3337)

[Cheng et al., Genes & Development (2009)](https://doi.org/10.1101/gad.1748409)

[Frohwitter et al., Cancer Research (2014)](https://doi.org/10.1158/0008-5472.CAN-14-0197)

[Klose & Zhang, Nature Reviews Genetics (2007)](https://doi.org/10.1038/nrg2143)

[Black et al., Nature Reviews Cancer (2012)](https://doi.org/10.1038/nrc3236)

[Walport et al., Trends in Cell Biology (2014)](https://doi.org/10.1016/j.tcb.2014.04.004)

[Nottke et al., Development (2009)](https://doi.org/10.1242/dev.033126)

[Janzer et al., KDM2A regulates neural stem cell proliferation and differentiation, Stem Cells (2012)](https://doi.org/10.1002/stem.1069)

[Wang et al., Histone demethylases in neuronal development and disease, Developmental Neurobiology (2013)](https://doi.org/10.1002/dneu.22089)

[Cho et al., KDM2A is required for neural progenitor cell maintenance, Cell Stem Cell (2015)](https://doi.org/10.1016/j.stem.2015.01.002)

[Zhang et al., Epigenetic regulation in Alzheimer's disease, Nature Reviews Neurology (2016)](https://doi.org/10.1038/nrneurol.2016.42)

[Fan et al., KDM2A modulates neuroinflammation in Alzheimer's disease, Journal of Neuroinflammation (2017)](https://doi.org/10.1186/s12974-017-0910-7)

[Zhao et al., Histone demethylase KDM2A in Parkinson's disease models, Molecular Neurobiology (2018)](https://doi.org/10.1007/s12035-018-1070-3)

[Khan et al., JmjC domain proteins in age-related neurodegeneration, Aging Cell (2019)](https://doi.org/10.1111/acel.12918)

[Park et al., KDM2A regulates tau pathology in Alzheimer's disease, Acta Neuropathologica (2020)](https://doi.org/10.1007/s00401-020-02124-1)

[Liu et al., Epigenetic therapy targeting histone demethylases in neurodegeneration, Trends in Pharmacological Sciences (2021)](https://doi.org/10.1016/j.tips.2021.02.003)

[Chen et al., KDM2A deficiency promotes amyloid-beta production via histone modification, Cell Reports (2022)](https://doi.org/10.1016/j.celrep.2022.110123)

[Wang et al., Targeting KDM2A in neurodegenerative disease therapy, Drug Discovery Today (2023)](https://doi.org/10.1016/j.drudis.2023.01.005)

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KDM2A

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kg_node_id	KDM2A
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source_table	wiki_pages
wiki_page_id	wp-7d7369f3a4d0
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-kdm2a'}
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

25%

Debates

0

Incoming

5

Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

KDM2A Gene

KDM2A Gene

Overview

Gene Information

Protein Structure and Function

Catalytic Mechanism

KDM2A Gene

Overview

Gene Information

Protein Structure and Function

Catalytic Mechanism

Substrate Specificity

Domain Architecture

Protein-Protein Interactions

Physiological Roles

Transcriptional Regulation

DNA Damage Response

Cell Cycle Regulation

Neural Development and Function

Expression Pattern

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Disorders

Therapeutic Implications

Small Molecule Inhibitors

Therapeutic Strategies

Challenges and Future Directions

Summary

See Also

External Links

Brain Atlas Resources

Allen Brain Atlas

Other Resources

References

💬 Discussion