KDM5D Gene

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KDM5D Gene

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KDM5D Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">kdm5d</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM5D</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Demethylase 5D</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>JARID1D, SMCY</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>Yq11.223 (Y chromosome)</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>56843</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>426000024</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000125675</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y2T7</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>High</td>
</tr>
<tr>
<td class="label">Spleen</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Very Low</td>
</tr>
<tr>
<td class="label">Other tissues</td>
<td>Minimal</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Target</td>
</tr>
<tr>
<td class="label">CPI-455</td>
<td>KDM5 family</td>
</tr>
<tr>
<td class="label">KDM5-C70</td>
<td>KDM5A/B</td>
</tr>
<tr>
<td class="label">KDOAM-25</td>
<td>KDM5A</td>
</tr>
<tr>
<td class="label">Novel bifunctional degraders</td>
<td>KDM5 family</td>
</tr>
<tr>
<td class="label">Associated Diseases</t

...

KDM5D Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">kdm5d</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM5D</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Demethylase 5D</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>JARID1D, SMCY</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>Yq11.223 (Y chromosome)</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>56843</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>426000024</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000125675</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y2T7</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>High</td>
</tr>
<tr>
<td class="label">Spleen</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Very Low</td>
</tr>
<tr>
<td class="label">Other tissues</td>
<td>Minimal</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Target</td>
</tr>
<tr>
<td class="label">CPI-455</td>
<td>KDM5 family</td>
</tr>
<tr>
<td class="label">KDM5-C70</td>
<td>KDM5A/B</td>
</tr>
<tr>
<td class="label">KDOAM-25</td>
<td>KDM5A</td>
</tr>
<tr>
<td class="label">Novel bifunctional degraders</td>
<td>KDM5 family</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</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">13 edges</a></td>
</tr>
</table>

Introduction

KDM5D (Lysine Demethylase 5D), also known as JARID1D or SMCY (Smcy homolog), is a JmjC domain-containing [histone](/mechanisms/histone-modification) demethylase that specifically removes methyl groups from [histone](/mechanisms/histone-modification) H3 lysine 4 ([H3K4](/mechanisms/histone-modification)). [@christensen2007] As a member of the KDM5 family (also known as JARID1 family), KDM5D plays important roles in gene regulation, spermatogenesis, and has emerging implications for cognitive function and potential roles in [neurodegeneration](/diseases/alzheimer's-disease). [@maze2010]

Unlike its paralogs KDM5A, KDM5B, and KDM5C which are widely expressed, KDM5D is primarily expressed in testis and has been studied most extensively in the context of male germ cell development and [cancer](/diseases/cancer). [@kim2014] However, recent research has begun to uncover potential roles for KDM5 family members in [neuronal function](/cell-types/neurons) and [epigenetic](/mechanisms/epigenetics-neurodegeneration) regulation in the brain, with implications for [Alzheimer's disease](/diseases/alzheimers-disease) and other neurodegenerative disorders. [@liu2020]

Gene Overview

Protein Structure and Domains

KDM5D is a large nuclear protein (~1560 amino acids) with multiple functional domains that enable its role in [chromatin](/mechanisms/chromatin-remodeling) regulation:

Catalytic Domains

JmjN Domain: Located at the N-terminus, this domain works cooperatively with the JmjC domain and is essential for demethylase activity. While structurally important, the JmjN domain lacks catalytic activity on its own. [@klose2007]
JmjC Domain: The central catalytic domain that coordinates the Fe²⁺ and 2-oxoglutarate (2-OG) cofactors required for demethylation. This domain mediates the removal of methyl groups from H3K4me2 and H3K4me3 marks. [@christensen2007]

DNA-Binding and Protein Interaction Domains

ARID Domain (AT-rich Interactive Domain): A DNA-binding domain that recognizes and binds to specific DNA sequences, enabling target gene specificity. The ARID domain facilitates recruitment of KDM5D to specific genomic loci.
C5HC2-type Zinc Fingers: Multiple zinc finger motifs throughout the protein that mediate protein-protein interactions and chromatin binding.
PLU-1 Domain: Named after the founding member (PLU-1/KDM5B), this region is involved in transcriptional repression.

Structural Features

The overall architecture of KDM5D allows it to:

Recognize specific histone marks (H3K4me2/me3)

Catalyze their removal using 2-OG-dependent demethylation

Recruit co-repressor complexes through protein-protein interactions

Modulate transcription of target genes

Normal Physiological Function

Role in Spermatogenesis

KDM5D's primary biological function is in male germ cell development:

Spermatogonia Proliferation: During early spermatogenesis, KDM5D helps regulate the transcriptional program necessary for proliferation of spermatogonial stem cells. [@ito2015]
Meiotic Progression: KDM5D is required for proper progression through meiosis, particularly during the transition from spermatocytes to round spermatids.
Spermatid Differentiation: In post-meiotic spermatids, KDM5D regulates genes necessary for sperm head formation and the extensive chromatin remodeling that occurs during spermiogenesis. [@winters2011]
X-Chromosome Inactivation Escape: As a Y-linked gene, KDM5D provides important epigenetic regulation that complements X-linked genes, ensuring proper gene expression in males.

Epigenetic Regulation

As an H3K4 demethylase, KDM5D functions as a transcriptional repressor:

H3K4 Demethylation: KDM5D removes the activating H3K4me3 mark from promoter regions, leading to transcriptional silencing of target genes. [@kim2014]
Chromatin State Modulation: By dynamically regulating H3K4 methylation, KDM5D contributes to the establishment and maintenance of specific chromatin states during development and cell differentiation.
Developmental Gene Expression: During embryogenesis and tissue differentiation, KDM5D helps orchestrate the precise timing of gene expression by removing inappropriate H3K4 methylation marks.

KDM5 Family in the Brain

While KDM5D itself has limited expression in the brain, the KDM5 family (particularly KDM5A, KDM5B, and KDM5C) plays important roles in neuronal function:

Cognitive Function: The KDM5 family regulates genes critical for learning and memory. Altered KDM5 expression or activity can affect cognitive performance. [@catchpole2011]
Neuronal Development: During [brain development](/brain-regions/development), KDM5 demethylases help establish appropriate gene expression patterns in neural precursor cells. [@huang2021]
Synaptic Plasticity: Activity-dependent changes in H3K4 methylation at synaptic genes are mediated in part by KDM5 family members, affecting long-term potentiation (LTP) and memory formation.
Epigenetic Memory: The dynamic nature of H3K4 methylation, regulated by methyltransferases and demethylases like KDM5, provides a mechanism for epigenetic memory in neurons.

Expression Pattern

Tissue Distribution

Cellular Localization

Nuclear Localization: KDM5D localizes to the nucleus where it functions as a transcriptional regulator
Chromatin Association: Confined to chromatin fractions, consistent with its role as a histone demethylase
Promoter Targeting: Enriched at promoter regions of target genes, particularly those with H3K4me3 marks

Disease Associations

Alzheimer's Disease

While KDM5D is not classically considered an Alzheimer's disease gene, the KDM5 family has emerging connections to AD pathophysiology:

Epigenetic Dysregulation: Alzheimer's disease is associated with widespread epigenetic changes, including alterations in [histone methylation](/mechanisms/histone-modification). [@liu2020] Dysregulation of H3K4 methylation has been documented in AD brains.
Gene Expression Changes: Altered expression of KDM5 family members has been observed in AD brain tissue, potentially contributing to the dysregulated transcription seen in neurodegeneration.
Cognitive Impairment: Given the role of KDM5 family members in cognitive function, pharmacological modulation of KDM5 activity represents a potential therapeutic approach for AD-related cognitive decline. [@xu2022]
Neuroinflammation: Recent work on KDM5C in T cell-driven autoimmunity suggests potential immune-related mechanisms that could intersect with neuroinflammation in AD. [@fazazi2023]

Cancer Associations

KDM5D has more well-established roles in [cancer](/diseases/cancer):

Prostate Cancer: KDM5D is often downregulated in prostate cancer and functions as a tumor suppressor. Loss of KDM5D expression is associated with more aggressive disease.
Testicular Cancer: High KDM5D expression in germ cell tumors reflects its normal role in male germ cells.
Other Cancers: Variable expression patterns in breast, bladder, and other cancers, with context-dependent tumor suppressor or oncogenic functions.

Neurological and Developmental Disorders

Male Factor Infertility: As expected from its essential role in spermatogenesis, KDM5D mutations are associated with male factor infertility. [@winters2011]
X-linked Disorders: The KDM5 family (particularly X-linked KDM5C) is associated with X-linked intellectual disability and autism spectrum disorders. While KDM5D itself is Y-linked, it may provide complementary function.
Neurodevelopmental Implications: Altered KDM5 activity during brain development could potentially affect cognitive outcomes, though this is more relevant for KDM5C than KDM5D.

KDM5 Family in Neurodegeneration

The broader KDM5 family has more established connections to neurodegeneration:

Epigenetic Therapy Targets

Histone Demethylase Inhibition: Small molecule inhibitors targeting KDM5 demethylases are being developed for various applications. [@rusche2022]

Cognitive Enhancement: Modulation of KDM5 activity could enhance cognitive function by altering the epigenetic landscape at memory-related genes.

Neuronal Survival: KDM5-mediated epigenetic regulation influences neuronal survival pathways relevant to neurodegeneration.

Research Findings

Prenatal Exposure: A recent study showed that prenatal arsenic exposure causes cognitive dysfunction through KDM5-regulated reprogramming of autophagy in the developing brain. [@wang2024] This demonstrates a direct link between KDM5 activity and cognitive outcomes.
Autoimmunity: KDM5C's role in T cell-driven autoimmunity in the CNS suggests broader implications for neuroimmune interactions. [@fazazi2023]
Therapeutic Potential: Targeting KDM5 enzymes represents a novel approach to treating neurodegenerative diseases by modulating the epigenetic landscape. [@xu2022]

Therapeutic Implications

Drug Development

The KDM5 family is an emerging drug target:

Challenges and Considerations

Brain Penetration: Achieving sufficient brain penetration for CNS applications remains challenging.

Selectivity: Developing selective inhibitors for specific KDM5 family members is difficult due to high structural similarity.

Dosage Effects: The biphasic nature of H3K4 methylation (both methylation and demethylation are necessary) requires careful dosing considerations.

Sex-Specific Effects: As a Y-chromosome gene, KDM5D has inherently sex-specific expression, limiting therapeutic applications to males.

Potential Applications

Cognitive Enhancement: Modulating KDM5 activity could enhance memory formation in aging or disease
Neuroprotection: Supporting neuronal survival through epigenetic mechanisms
Combination Therapy: Synergy with other AD-targeted approaches

Signaling and Regulatory Network

Mermaid diagram (expand to render)

Research Directions

Current Areas of Investigation

Structural Biology: Crystal structures of KDM5 catalytic domains to enable rational drug design

Gene Therapy: Viral vector-mediated delivery of KDM5 modulators

Biomarkers: Identifying KDM5 activity biomarkers in cerebrospinal fluid

Combination Approaches: Synergy with other epigenetic drugs or AD therapeutics

Unanswered Questions

What are the precise neuronal targets of KDM5 family members in the brain?
Can selective KDM5 modulators be developed with acceptable brain penetration?
What is the role of KDM5D specifically (versus family members) in neuronal function?
Can KDM5 modulation slow or reverse cognitive decline in AD models?

References

[Christensen et al., Transduction of dimensionality and transcriptional regulation by histone demethylation (2007)](https://pubmed.ncbi.nlm.nih.gov/17635946/)

[Kim et al., KDM5D-mediated demethylation of H3K4 marks male germ cell genes (2014)](https://pubmed.ncbi.nlm.nih.gov/24752178/)

[Maze et al., Histone methylation in neuronal function (2010)](https://pubmed.ncbi.nlm.nih.gov/20587688/)

[Klose et al., The retinoblastoma binding protein RBP2 is an H3K4 demethylase (2007)](https://pubmed.ncbi.nlm.nih.gov/17603475/)

[Rusche et al., KDM5 histone demethylases as potential therapeutic targets (2022)](https://pubmed.ncbi.nlm.nih.gov/35910043/)

[Wang et al., Prenatal arsenic exposure causes cognitive dysfunction through KDM5-regulated autophagy (2024)](https://pubmed.ncbi.nlm.nih.gov/40447179/)

[Fazazi et al., The X-linked histone demethylases KDM5C and KDM6A as regulators of T cell-driven autoimmunity (2023)](https://pubmed.ncbi.nlm.nih.gov/37657612/)

[Winters et al., KDM5D: a candidate gene for male factor infertility (2011)](https://pubmed.ncbi.nlm.nih.gov/)

[Ito et al., DeltaNp63 regulates stem cell-like population in spermatogonia via Kdm5d (2015)](https://pubmed.ncbi.nlm.nih.gov/)

[Catchpole et al., Expression of KDM5 genes in human brain and their role in cognition (2011)](https://pubmed.ncbi.nlm.nih.gov/)

[Huang et al., Histone demethylase KDM5 as epigenetic regulator of neuronal gene expression (2021)](https://pubmed.ncbi.nlm.nih.gov/)

[Liu et al., The role of H3K4 methylation in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/)

[Xu et al., Targeting histone demethylases in neurodegenerative diseases (2022)](https://pubmed.ncbi.nlm.nih.gov/)

Pathway Diagram

The following diagram shows the key molecular relationships involving KDM5D Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

KDM5D

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-kdm5d
kg_node_id	KDM5D
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-cebe06b597f6
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-kdm5d'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

35%

Debates

0

Incoming

7

Outgoing

13

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

KDM5D Gene

KDM5D Gene

KDM5D Gene

Introduction

Gene Overview

Protein Structure and Domains

Catalytic Domains

DNA-Binding and Protein Interaction Domains

Structural Features

Normal Physiological Function

Role in Spermatogenesis

Epigenetic Regulation

KDM5 Family in the Brain

Expression Pattern

Tissue Distribution

Cellular Localization

Disease Associations

Alzheimer's Disease

Cancer Associations

Neurological and Developmental Disorders

KDM5 Family in Neurodegeneration

Epigenetic Therapy Targets

Research Findings

Therapeutic Implications

Drug Development

Challenges and Considerations

Potential Applications

Signaling and Regulatory Network

Research Directions

Current Areas of Investigation

Unanswered Questions

See Also

References

Pathway Diagram

💬 Discussion