KDM4C

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KDM4C

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KDM4C

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">KDM4C</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Demethylase 4C</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM4C</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>JMJD2C, GASC1, TDRD14C</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>9p24.1</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[605469](https://omim.org/entry/605469)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q9H3R0](https://www.uniprot.org/uniprot/Q9H3R0)</td>
</tr>
<tr>
<td class="label">HGNC</td>
<td>[17071](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:17071)</td>
</tr>
<tr>
<td class="label">Entrez Gene</td>
<td>[23081](https://www.ncbi.nlm.nih.gov/gene/23081)</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>[ENSG00000107077](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000107077)</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs2296067</td>
<td>Intronic SNP</td>
</tr>
<tr>
<td class="label">9p24.1 amplification</td>
<td>CNV</td>
</tr>
<tr>
<td class="label">p.H190A</td>
<td>Missense (JmjC)</td>
</tr>
<tr>
<td class="label">p.R919W</td>
<td>Missense (Tudor)</td>
</tr>
<tr>
<td class="label">KG Connections</td

...

KDM4C

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">KDM4C</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Demethylase 4C</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM4C</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>JMJD2C, GASC1, TDRD14C</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>9p24.1</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[605469](https://omim.org/entry/605469)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q9H3R0](https://www.uniprot.org/uniprot/Q9H3R0)</td>
</tr>
<tr>
<td class="label">HGNC</td>
<td>[17071](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:17071)</td>
</tr>
<tr>
<td class="label">Entrez Gene</td>
<td>[23081](https://www.ncbi.nlm.nih.gov/gene/23081)</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>[ENSG00000107077](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000107077)</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs2296067</td>
<td>Intronic SNP</td>
</tr>
<tr>
<td class="label">9p24.1 amplification</td>
<td>CNV</td>
</tr>
<tr>
<td class="label">p.H190A</td>
<td>Missense (JmjC)</td>
</tr>
<tr>
<td class="label">p.R919W</td>
<td>Missense (Tudor)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

KDM4C

</div>

Overview

KDM4C is a human gene. Variants in KDM4C have been implicated in Alzheimer's Disease, Huntington's Disease, Parkinson's Disease. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

KDM4C (Lysine Demethylase 4C), also known as JMJD2C or GASC1, encodes a JmjC domain-containing histone demethylase that removes di- and trimethyl marks from histone H3 lysine 9 (H3K9me2/3) and histone H3 lysine 36 (H3K36me2/3). KDM4C is a transcriptional coactivator that counteracts heterochromatin formation by erasing the repressive H3K9me3 mark deposited by [SUV39H1](/genes/suv39h1), [SUV39H2](/genes/suv39h2), and [SETDB1](/genes/setdb1).[1] In [neurons](/entities/neurons), KDM4C dynamically regulates heterochromatin boundaries, gene activation during synaptic plasticity, and DNA damage response pathways. Aberrant KDM4C activity contributes to heterochromatin erosion during aging, a hallmark of neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease) and [Huntington's disease](/diseases/huntington-disease).

Function and Mechanism

KDM4C contains a JmjN domain, a catalytic JmjC domain, two PHD fingers, and two Tudor domains. The Tudor domains recognize methylated histones (H3K4me3 and H4K20me2/3), enabling context-dependent recruitment, while the PHD fingers contribute to chromatin binding and protein-protein interactions.

H3K9me2/3 Demethylation

KDM4C catalyzes Fe(II)- and 2-oxoglutarate-dependent oxidative demethylation of H3K9me2 and H3K9me3, converting them to H3K9me1. H3K9me3 is the hallmark of constitutive heterochromatin (deposited by [SUV39H1](/genes/suv39h1)/[SUV39H2](/genes/suv39h2)) and facultative heterochromatin/euchromatic silencing (deposited by [SETDB1](/genes/setdb1)). By removing H3K9me3, KDM4C prevents [CBX5](/genes/cbx5) (HP1α) binding and heterochromatin spreading, maintaining euchromatic gene accessibility.[1]

H3K36me2/3 Demethylation

KDM4C also demethylates H3K36me2 and H3K36me3, distinguishing it from [KDM2B](/genes/kdm2b) which only targets H3K36me1/2. H3K36me3 is deposited co-transcriptionally by [SETD2](/genes/setd2) and marks actively transcribed gene bodies. KDM4C-mediated H3K36me3 demethylation at gene bodies can modulate transcriptional elongation, alternative splicing, and DNA repair pathway choice.[2]

Synaptic Plasticity and Memory

In hippocampal neurons, KDM4C is recruited to immediate early gene (IEG) promoters — including Arc, Fos, and Bdnf — following neuronal activation. KDM4C-mediated H3K9me3 demethylation at these loci is required for rapid transcriptional induction during [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and memory consolidation. Inhibition of KDM4C blocks activity-dependent gene expression and impairs spatial memory formation.[3]

DNA Damage Response

KDM4C is rapidly recruited to DNA double-strand breaks (DSBs) where it demethylates H3K9me3 and H3K36me3 to facilitate repair factor access. This function is particularly important in post-mitotic neurons that accumulate DNA damage with aging and rely heavily on non-homologous end joining (NHEJ) for DSB repair.[4]

Disease Associations

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), KDM4C overactivation at heterochromatic regions leads to pathological erosion of constitutive heterochromatin, derepression of repetitive elements (LINE-1, SINE, satellite repeats), and genomic instability in aging neurons. Paradoxically, KDM4C activity at IEG promoters declines, impairing activity-dependent transcription. This dual dysregulation — excess activity at heterochromatin, insufficient activity at euchromatic targets — reflects age-related redistribution of KDM4C from euchromatin to heterochromatin.[5]

The interaction between KDM4C and [tau](/proteins/tau) pathology is mediated through [tau](/proteins/tau)'s chromatin-binding function: hyperphosphorylated tau disrupts heterochromatin independently of KDM4C, but KDM4C-mediated H3K9me3 loss amplifies tau-induced heterochromatin relaxation, creating a feedforward loop of epigenomic instability.[5]

Huntington's Disease

In [Huntington's disease](/diseases/huntington-disease), mutant [huntingtin protein](/proteins/huntingtin) sequesters KDM4C in cytoplasmic aggregates, depleting nuclear KDM4C and causing aberrant accumulation of H3K9me3 at normally active gene promoters. This contributes to the transcriptional dysregulation characteristic of HD striatal neurons, particularly affecting genes in the BDNF and glutamate signaling pathways.[6]

Parkinson's Disease

Dopaminergic neurons of the substantia nigra exhibit age-dependent changes in KDM4C expression that correlate with heterochromatin remodeling. In [Parkinson's disease](/diseases/parkinsons-disease), [alpha-synuclein](/proteins/alpha-synuclein) accumulation in the nucleus alters KDM4C chromatin occupancy, contributing to the epigenomic signature of PD-vulnerable neurons.[7]

Intellectual Disability

Heterozygous loss-of-function variants in KDM4C cause a neurodevelopmental syndrome featuring intellectual disability, speech delay, and behavioral abnormalities. These variants impair JmjC catalytic activity, leading to excessive H3K9me3 accumulation at developmental gene promoters and delayed neuronal maturation.[8]

Expression in the Nervous System

KDM4C is ubiquitously expressed in the brain with enrichment in the [hippocampus](/brain-regions/hippocampus) (CA1, CA3, dentate gyrus), prefrontal [cortex](/brain-regions/cortex), amygdala, and striatum — regions central to memory, cognition, and motor control. Nuclear KDM4C is concentrated in euchromatic compartments in young neurons but redistributes to heterochromatic foci during aging.[3]

At the single-cell level, KDM4C is most highly expressed in excitatory neurons and oligodendrocytes, with moderate expression in inhibitory interneurons and [astrocytes](/entities/astrocytes). Microglial KDM4C expression increases during neuroinflammatory activation, where it facilitates derepression of pro-inflammatory gene programs.[7]

Common Variants

Therapeutic Implications

KDM4C is a druggable target due to its dependence on Fe(II) and 2-oxoglutarate cofactors. Several JmjC domain inhibitors — including JIB-04, QC6352, and TACH101 — inhibit KDM4 family enzymes and have shown neuroprotective effects in preclinical models by preventing heterochromatin erosion in aging neurons.[9]

For neurodegenerative diseases, selective KDM4C inhibition could preserve constitutive heterochromatin integrity and reduce repetitive element derepression. However, complete KDM4C inhibition would impair activity-dependent gene expression required for synaptic plasticity. Context-selective strategies — such as targeting KDM4C-heterochromatin interactions while preserving KDM4C-euchromatin functions — are needed. The Tudor domains, which mediate KDM4C recruitment to specific chromatin contexts, represent potential allosteric drug targets.[9]

The connection between KDM4C and [KDM4B](/genes/kdm4b) (which shares substrate specificity) suggests compensatory mechanisms that must be considered in therapeutic design. Dual KDM4B/C inhibitors may be more effective than selective inhibitors for heterochromatin maintenance.[10]

External Links

[OMIM: 605469](https://omim.org/entry/605469)
[GeneCards: KDM4C](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDM4C)
[UniProt: Q9H3R0](https://www.uniprot.org/uniprot/Q9H3R0)
[Allen Brain Atlas: KDM4C](https://portal.brain-map.org/search?query=KDM4C)
[GTEx Portal: KDM4C](https://gtexportal.org/home/gene/KDM4C)

References

[Cloos et al., The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3 (2006) (2006)](https://doi.org/10.1038/nature04837)

[Unknown, Berry & Bhatt, H3K36 methylation and demethylation by KDM4 enzymes regulate gene body function (2019) (2019)](https://doi.org/10.1016/j.tig.2019.02.002)

[Webb et al., Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex during memory consolidation (2017) (2017)](https://doi.org/10.1016/j.nlm.2017.02.007)

[Khoury-Haddad et al., The emerging role of lysine demethylases in DNA damage response (2015) (2015)](https://doi.org/10.1016/j.dnarep.2015.09.016)

[Frost et al., Tau promotes neurodegeneration through global chromatin relaxation (2014) (2014)](https://doi.org/10.1038/nn.3639)

[Vashishtha et al., Targeting H3K4 trimethylation in Huntington disease (2013) (2013)](https://doi.org/10.1073/pnas.1311323110)

[Unknown, Basavarajappa & Bhatt, Epigenetic mechanisms in neurological and neurodegenerative diseases (2021) (2021)](https://doi.org/10.3389/fgene.2021.747927)

[Unknown, Deciphering Developmental Disorders Study, Prevalence and architecture of de novo mutations in developmental disorders (2017) (2017)](https://doi.org/10.1038/nature21062)

[Vinogradova et al., An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells (2016) (2016)](https://doi.org/10.1038/nchembio.2085)

[Johansson et al., Structural analysis of human KDM5B guides histone demethylase inhibitor development (2016) (2016)](https://doi.org/10.1038/nsmb.3270)

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Related Entities

KDM4C

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-kdm4c
kg_node_id	KDM4C
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-6a665ca32a86
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-kdm4c'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

20%

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4

Outgoing

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📗 Cite This Artifact

KDM4C

KDM4C

KDM4C

Overview

Function and Mechanism

H3K9me2/3 Demethylation

H3K36me2/3 Demethylation

Synaptic Plasticity and Memory

DNA Damage Response

Disease Associations

Alzheimer's Disease

Huntington's Disease

Parkinson's Disease

Intellectual Disability

Expression in the Nervous System

Common Variants

Therapeutic Implications

See Also

External Links

References

💬 Discussion