KDM5B (Lysine Demethylase 5B)

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KDM5B (Lysine Demethylase 5B)

<div class="infobox infobox-gene">
<h3>KDM5B</h3>
<table> [@vallianatos2018]
<tr><td><strong>Full Name</strong></td><td>Lysine Demethylase 5B</td></tr> [@wynder2005]
<tr><td><strong>Gene Symbol</strong></td><td>KDM5B</td></tr> [@harmeyer2017]
<tr><td><strong>Aliases</strong></td><td>JARID1B, PLU1, RBP2-H1</td></tr> [@dey2012]
<tr><td><strong>Chromosomal Location</strong></td><td>1q32.1</td></tr> [@vinogradova2016]
<tr><td><strong>NCBI Gene ID</strong></td><td>[10765](https://www.ncbi.nlm.nih.gov/gene/10765)</td></tr> [@tang2022]
<tr><td><strong>OMIM</strong></td><td>[605393](https://omim.org/entry/605393)</td></tr> [@johansson2014]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000117139](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117139)</td></tr> [@scandaglia2017]
<tr><td><strong>UniProt</strong></td><td>[Q9UGL1](https://www.uniprot.org/uniprot/Q9UGL1)</td></tr>
<tr><td><strong>Protein</strong></td><td>Lysine-specific demethylase 5B</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), intellectual disability, autism spectrum disorder, [Parkinson's disease](/diseases/parkinsons-disease)</td></tr>
</table>
</div>

Overview

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KDM5B (Lysine Demethylase 5B)

Overview

Mermaid diagram (expand to render)

BDNF is a human gene. Variants in BDNF have been implicated in Intellectual Disability and Autism Spectrum Disorder, 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.

Gene Function

KDM5B (also known as JARID1B or PLU1) encodes a Jumonji C (JmjC) domain-containing histone demethylase that specifically removes di- and trimethyl marks from histone H3 lysine 4 (H3K4me2/3). H3K4me3 is the canonical activating mark at gene promoters, and its removal by KDM5B serves as a critical transcriptional OFF switch. KDM5B thus functions as a transcriptional repressor that fine-tunes gene expression by modulating the dynamic balance between H3K4 methylation and demethylation.

KDM5B is a large (1544 amino acid) multidomain protein:

JmjN + JmjC domains: Together form the catalytic core; JmjC contains the Fe(II) and α-ketoglutarate (2-OG) binding sites required for oxidative demethylation
ARID domain: An AT-rich interaction domain that binds DNA, providing sequence-specific targeting to CCGCCC motifs enriched at CpG island promoters
PHD fingers (3x): PHD1 reads unmethylated H3K4 (product recognition), PHD2 and PHD3 bind H3K4me3 (substrate recognition), enabling allosteric activation upon engagement with trimethylated substrates
C5HC2 zinc finger: Mediates protein-protein interactions for complex formation

KDM5B regulates neural gene expression through multiple mechanisms:

Promoter H3K4me3 removal: KDM5B demethylates H3K4me3 at promoters of non-neural genes during neuronal differentiation, enabling silencing of progenitor programs as [neurons](/entities/neurons) mature
Enhancer regulation: KDM5B removes H3K4me3 from enhancers, converting them from active (H3K4me3+) to poised (H3K4me1+) state; this enhancer decommissioning is critical during neural lineage transitions
Bivalent domain maintenance: At bivalent promoters (bearing both H3K4me3 and H3K27me3), KDM5B fine-tunes H3K4me3 levels to maintain genes in a poised state, ready for rapid activation or silencing during neural differentiation
Transposable element silencing: KDM5B cooperates with the KAP1/TRIM28 co-repressor complex to silence retrotransposons in neural cells, preventing genomic instability
Circadian rhythm regulation: KDM5B demethylates H3K4me3 at clock gene promoters, contributing to circadian oscillations of neural gene expression

Neural Expression and Brain Distribution

KDM5B shows widespread brain expression with notable regional enrichment:

[Hippocampus](/brain-regions/hippocampus): High expression in granule cells of the dentate gyrus and CA3 pyramidal neurons, regions critical for pattern separation and memory consolidation
[Cortex](/brain-regions/cortex): Expression in pyramidal neurons across all layers, with enrichment in layer 2/3 and layer 5 neurons
Cerebellum: Strong Purkinje cell expression, where KDM5B regulates cerebellar developmental gene programs
Substantia nigra: Expression in dopaminergic neurons, relevant to Parkinson's disease vulnerability
Neural stem cells: High expression in adult neural stem cells in the subventricular zone and subgranular zone, where KDM5B regulates stem cell quiescence

Disease Associations

Intellectual Disability and Autism Spectrum Disorder

De novo loss-of-function mutations in KDM5B are associated with autosomal dominant intellectual disability and autism spectrum disorder (ASD). Affected individuals present with:

Mild to moderate intellectual disability
Speech and language delay
Behavioral abnormalities including ASD features
Variable dysmorphic features

KDM5B knockout mice show impaired hippocampal-dependent learning, reduced dendritic spine density, and altered excitatory/inhibitory balance, providing mechanistic insight into these phenotypes.

Alzheimer's Disease

KDM5B has multiple connections to [AD](/diseases/alzheimers-disease):

Epigenetic aging: KDM5B expression increases with age in [microglia](/cell-types/microglia-neuroinflammation), leading to excessive H3K4me3 removal at neuroprotective gene promoters including [BDNF](/genes/bdnf), [NTRK2](/genes/ntrk2), and synaptic plasticity genes
[Tau](/proteins/tau) pathology: KDM5B-mediated removal of H3K4me3 at the [MAPT](/genes/mapt) locus is disrupted in AD neurons, contributing to aberrant tau expression
Microglial polarization: KDM5B regulates the epigenetic switch between homeostatic and disease-associated microglia (DAM) by demethylating H3K4me3 at inflammatory gene promoters
Amyloid response genes: KDM5B occupies promoters of amyloid-responsive genes including [TREM2](/genes/trem2) and [TYROBP](/genes/tyrobp), modulating microglial phagocytic capacity

Parkinson's Disease

Dopaminergic vulnerability: KDM5B-mediated H3K4me3 removal at dopaminergic neuron survival genes ([NURR1](/genes/nr4a2), [PITX3](/genes/pitx3)) may contribute to selective vulnerability of substantia nigra neurons in [PD](/diseases/parkinsons-disease)
Mitochondrial gene regulation: KDM5B demethylates H3K4me3 at nuclear-encoded mitochondrial genes, and KDM5B dysregulation impairs mitochondrial biogenesis in dopaminergic neurons
Alpha-synuclein stress: [Alpha-synuclein](/proteins/alpha-synuclein) aggregates alter KDM5B nuclear localization, disrupting the H3K4me3 landscape in affected neurons

Common Variants

| Variant | Type | Population Frequency | Clinical Significance |
|---------|------|---------------------|----------------------|
| p.Arg1399Ter | Nonsense | Rare | Intellectual disability |
| p.Cys1177Tyr | Missense | Rare | ASD, developmental delay |
| rs1030421 | Intronic | 0.35 (global) | Cognitive performance GWAS |
| p.Pro1199Leu | Missense | Rare | Likely pathogenic (NDD) |

Therapeutic Implications

KDM5 inhibitors: Small-molecule KDM5 inhibitors (CPI-455, KDM5-C70, KDOAM-25) are in preclinical development for cancer; potential repurposing for neurodegeneration by preserving H3K4me3 at neuroprotective loci
JmjC domain inhibitors: Broad JmjC domain inhibitors (2-OG analogues) inhibit KDM5B activity; selectivity challenges due to the large JmjC demethylase family
Neuroprotective H3K4me3 preservation: Partial KDM5B inhibition could maintain H3K4me3 at BDNF, NTRK2, and synaptic gene promoters, supporting neuronal survival in AD and PD
Combination with [HDAC](/entities/hdac-enzymes) inhibitors: KDM5B inhibition combined with HDAC inhibitors could synergistically increase expression of neuroprotective genes silenced in neurodegeneration
Biomarker potential: H3K4me3 changes at KDM5B target genes in peripheral blood cells may serve as epigenetic biomarkers for neurodegenerative disease progression

External Links

[NCBI Gene: KDM5B](https://www.ncbi.nlm.nih.gov/gene/10765)
[GeneCards: KDM5B](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDM5B)
[OMIM: 605393](https://omim.org/entry/605393)
[UniProt: Q9UGL1](https://www.uniprot.org/uniprot/Q9UGL1)
[Allen Brain Atlas: KDM5B](https://portal.brain-map.org/)

References

[Catchpole et al., PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells (2011) (2011)](https://doi.org/10.1016/j.biocel.2011.07.010)

[Albert et al., Histone demethylase KDM5B regulates embryonic stem cell self-renewal (2013) (2013)](https://doi.org/10.1073/pnas.1302800110)

[Vallianatos et al., Altered gene-regulatory function of KDM5C by a novel mutation associated with autism and intellectual disability (2018) (2018)](https://doi.org/10.3389/fnmol.2018.00104)

[Wynder et al., Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation (2005) (2005)](https://doi.org/10.1038/ncb1210)

[Harmeyer et al., JARID1 histone demethylases: emerging targets in cancer (2017) (2017)](https://doi.org/10.1016/j.tips.2017.02.001)

[Dey et al., Loss of the tumor suppressor BAP1 causes myeloid transformation (2012) (2012)](https://doi.org/10.1126/science.1221711)

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

[Tang et al., KDM5B and H3K4 trimethylation in neurodevelopmental and neurodegenerative disorders (2022) (2022)](https://doi.org/10.1016/j.nbd.2022.105697)

[Johansson et al., A role for KDM5B in maintenance of gene expression and neural stem cell identity (2014) (2014)](https://doi.org/10.1016/j.celrep.2014.03.067)

[Scandaglia et al., Loss of Kdm5c causes spurious transcription and prevents the fine-tuning of activity-regulated enhancers in neurons (2017) (2017)](https://doi.org/10.1016/j.celrep.2017.05.015)

Pathway Diagram

The following diagram shows the key molecular relationships involving KDM5B (Lysine Demethylase 5B) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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KDM5B (Lysine Demethylase 5B)

KDM5B (Lysine Demethylase 5B)

Overview

KDM5B (Lysine Demethylase 5B)

Overview

Gene Function

Neural Expression and Brain Distribution

Disease Associations

Intellectual Disability and Autism Spectrum Disorder

Alzheimer's Disease

Parkinson's Disease

Common Variants

Therapeutic Implications

See Also

External Links

References

Pathway Diagram