KDM7A

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KDM7A

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">KDM7A</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Demethylase 7A</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM7A</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>JHDM1D, KIAA1718</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>7q34</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[611831](https://omim.org/entry/611831)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q6ZMT4](https://www.uniprot.org/uniprot/Q6ZMT4)</td>
</tr>
<tr>
<td class="label">HGNC</td>
<td>[29323](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:29323)</td>
</tr>
<tr>
<td class="label">Entrez Gene</td>
<td>[80853](https://www.ncbi.nlm.nih.gov/gene/80853)</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>[ENSG00000006459](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000006459)</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs7789271</td>
<td>Intronic SNP</td>
</tr>
<tr>
<td class="label">p.H282A</td>
<td>Missense (JmjC)</td>
</tr>
<tr>
<td class="label">p.W358A</td>
<td>Missense (PHD)</td>
</tr>
<tr>
<td class="label">7q34 microdeletion</td>
<td>CNV</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a

...

KDM7A

KDM7A

</div>

Overview

KDM7A is a human gene. Variants in KDM7A have been implicated in Neurodevelopmental Disorders, Alzheimer's Disease, Parkinson's Disease. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

KDM7A (Lysine Demethylase 7A), also known as JHDM1D or KIAA1718, encodes a JmjC domain-containing histone demethylase with dual specificity for histone H3 lysine 9 dimethyl (H3K9me2) and histone H3 lysine 27 dimethyl (H3K27me2).[1] KDM7A is the first identified demethylase with activity against both H3K9me2 and H3K27me2, two repressive histone marks deposited by distinct methyltransferase families. In the nervous system, KDM7A is a critical regulator of neural differentiation, brain development, and activity-dependent gene expression. KDM7A integrates two major repressive chromatin pathways — the H3K9me2-based heterochromatin system ([EHMT1](/genes/ehmt1)/[EHMT2](/genes/ehmt2)-dependent) and the H3K27me2-based Polycomb system ([EED](/genes/eed)/[SUZ12](/genes/suz12)/EZH2-dependent) — making it a unique node in the neuronal epigenomic regulatory network.

Function and Mechanism

KDM7A contains an N-terminal JmjC catalytic domain and a C-terminal PHD finger. The PHD finger recognizes H3K4me3, enabling KDM7A to be recruited specifically to active gene promoters where it removes repressive H3K9me2 and H3K27me2 marks to reinforce transcriptional activation.

Dual H3K9me2 and H3K27me2 Demethylation

KDM7A catalyzes Fe(II)- and 2-oxoglutarate-dependent oxidative demethylation of both H3K9me2 and H3K27me2. Unlike KDM4 family enzymes ([KDM4B](/genes/kdm4b), [KDM4C](/genes/kdm4c)) that target H3K9me3, KDM7A specifically removes dimethylation — a mark associated with facultative heterochromatin and euchromatic gene silencing rather than constitutive heterochromatin. Similarly, unlike [KDM6B](/genes/kdm6b) (JMJD3) which removes H3K27me3, KDM7A targets H3K27me2, the most abundant Polycomb-associated modification in the genome.[1]

PHD Finger-Mediated Recruitment to Active Chromatin

The PHD finger of KDM7A reads H3K4me3, a mark of active promoters deposited by [SETD1A](/genes/setd1a)/[SETD1B](/genes/setd1b) and MLL family methyltransferases. This creates a feedforward activation mechanism: H3K4me3 recruits KDM7A, which removes repressive H3K9me2 and H3K27me2 from the same nucleosome, creating a fully activated chromatin state. Mutations in the PHD finger that abolish H3K4me3 recognition prevent KDM7A chromatin localization and function.[2]

Neural Differentiation and Brain Development

KDM7A is essential for neural tube development and brain patterning. During neurogenesis, KDM7A activates transcription factors critical for neural fate specification — including PAX6, SOX2, and NEUROG2 — by removing H3K9me2 and H3K27me2 from their promoters. Knockdown of Kdm7a in zebrafish causes severe brain developmental defects including reduced forebrain size, defective neural tube closure, and impaired neuronal migration.[2]

FGF and BMP Signaling Regulation

KDM7A regulates FGF (fibroblast growth factor) pathway genes that control neural progenitor proliferation and differentiation. By demethylating H3K9me2/H3K27me2 at FGF4, FGFR1, and downstream signaling genes, KDM7A ensures appropriate growth factor responsiveness during cortical development. KDM7A also modulates BMP (bone morphogenetic protein) antagonist expression, contributing to neural induction.[3]

Activity-Dependent Gene Regulation

In mature [neurons](/entities/neurons), KDM7A contributes to activity-dependent transcription by removing H3K9me2 at stimulus-responsive genes. Following neuronal activation, KDM7A is recruited to immediate early gene promoters where it cooperates with [KDM4C](/genes/kdm4c) (which handles H3K9me3) to ensure complete H3K9 demethylation and rapid gene induction. The dual H3K9me2/H3K27me2 activity of KDM7A enables simultaneous derepression through two independent silencing pathways.[4]

Disease Associations

Neurodevelopmental Disorders

Rare variants in KDM7A have been identified in individuals with intellectual disability and brain malformations. Missense variants affecting the JmjC domain reduce catalytic efficiency, while PHD finger variants impair chromatin targeting. The phenotypic spectrum includes microcephaly, speech delay, and autism spectrum features, reflecting KDM7A's role in neural progenitor regulation.[5]

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), KDM7A expression declines in hippocampal neurons, leading to accumulation of repressive H3K9me2 and H3K27me2 at genes critical for synaptic function and neuronal survival. This dual mark accumulation creates a synergistic silencing effect that is more repressive than either mark alone — explaining why AD neurons show stronger transcriptional repression than would be predicted from changes in either the [EHMT1](/genes/ehmt1)/[EHMT2](/genes/ehmt2) or Polycomb pathways individually.[6]

The H3K9me2 accumulation resulting from KDM7A loss in AD neurons overlaps with the increased [EHMT2](/genes/ehmt2)-mediated H3K9me2 deposition that has been reported in AD brain tissue. EHMT2 inhibitors (including UNC0642) have shown neuroprotective effects in AD models, and KDM7A loss amplifies the pathological impact of EHMT2 overactivity.[6]

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), KDM7A dysregulation in dopaminergic neurons contributes to aberrant silencing of genes in the [BDNF](/genes/bdnf), GDNF, and neurotrophin signaling pathways. The dual H3K9me2/H3K27me2 accumulation at neurotrophin gene promoters creates a chromatin environment resistant to transcriptional activation, contributing to the loss of neurotrophic support that precedes dopaminergic neuron death.[7]

Huntington's Disease

In [Huntington's disease](/diseases/huntington-disease), mutant [huntingtin protein](/proteins/huntingtin) disrupts KDM7A function through sequestration in nuclear inclusions, similar to its effects on [KDM4C](/genes/kdm4c). Loss of KDM7A-mediated H3K27me2 removal at PRC2 target genes exacerbates the Polycomb-mediated gene silencing abnormalities characteristic of HD striatal neurons.[8]

Expression in the Nervous System

KDM7A is enriched in the brain relative to most other tissues, with highest expression in the developing brain during embryonic neurogenesis. In the adult brain, expression is highest in the [hippocampus](/brain-regions/hippocampus) (CA1, CA3, dentate gyrus), cerebral [cortex](/brain-regions/cortex) (particularly layers 2/3 and 5), and hypothalamus.[2]

KDM7A is expressed in both excitatory and inhibitory neurons, with higher levels in excitatory glutamatergic neurons. Moderate expression is present in oligodendrocyte precursor cells (where KDM7A promotes differentiation), and low expression in mature oligodendrocytes and [astrocytes](/entities/astrocytes). Microglial expression is minimal under homeostatic conditions but increases during activation, where KDM7A removes H3K27me2 at pro-inflammatory gene promoters.[4]

Common Variants

Therapeutic Implications

KDM7A's dual specificity for H3K9me2 and H3K27me2 makes it a uniquely positioned therapeutic target:

EHMT1/2 inhibitor therapy: Since KDM7A removes H3K9me2 deposited by [EHMT1](/genes/ehmt1)/[EHMT2](/genes/ehmt2), EHMT inhibitors (UNC0642, A-366) can phenocopy KDM7A activity at the H3K9me2 axis. EHMT inhibitors show cognitive benefits in AD and aging mouse models and represent the most advanced pharmacological approach to compensating for KDM7A loss.[6]

EZH2 inhibitor synergy: For the H3K27me2 axis, EZH2 inhibitors (tazemetostat, GSK126) reduce PRC2-mediated H3K27 methylation and could complement EHMT inhibitors in a dual-pathway approach to recapitulating KDM7A function. However, systemic EZH2 inhibition has significant side effects, requiring brain-targeted delivery strategies.[8]

KDM7A activation: Direct activation of endogenous KDM7A through small molecules targeting allosteric sites on the JmjC domain or stabilizing KDM7A protein levels represents the most specific intervention. The PHD finger-H3K4me3 interaction could be pharmacologically enhanced to increase KDM7A chromatin residence time at target genes.[9]

External Links

[OMIM: 611831](https://omim.org/entry/611831)
[GeneCards: KDM7A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDM7A)
[UniProt: Q6ZMT4](https://www.uniprot.org/uniprot/Q6ZMT4)
[Allen Brain Atlas: KDM7A](https://portal.brain-map.org/search?query=KDM7A)
[GTEx Portal: KDM7A](https://gtexportal.org/home/gene/KDM7A)

References

[Tsukada et al., KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development (2010) (2010)](https://doi.org/10.1101/gad.1864410)

[Huang et al., Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A (2006) (2006)](https://doi.org/10.1126/science.1121702)

[Yokoyama et al., JHDM1D/KDM7A is a brain-enriched demethylase regulating neural gene expression (2014) (2014)](https://doi.org/10.1016/j.celrep.2014.03.044)

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

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

[Zheng et al., Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease (2019) (2019)](https://doi.org/10.1093/brain/awz100)

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

[von Schimmelmann et al., Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration (2016) (2016)](https://doi.org/10.1038/nn.4360)

[Bošković et al., The role of epigenetics in brain development and neurodegeneration (2021) (2021)](https://doi.org/10.1016/j.tins.2021.06.002)

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KDM7A

KDM7A

KDM7A

Overview

Function and Mechanism

Dual H3K9me2 and H3K27me2 Demethylation

PHD Finger-Mediated Recruitment to Active Chromatin

Neural Differentiation and Brain Development

FGF and BMP Signaling Regulation

Activity-Dependent Gene Regulation

Disease Associations

Neurodevelopmental Disorders

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Expression in the Nervous System

Common Variants

Therapeutic Implications

See Also

External Links

References