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| Full Name | Lysine Demethylase 5B |
| Gene Symbol | KDM5B |
| Aliases | JARID1B, PLU1, RBP2-H1 |
| Chromosomal Location | 1q32.1 |
| NCBI Gene ID | [10765](https://www.ncbi.nlm.nih.gov/gene/10765) |
| OMIM | [605393](https://omim.org/entry/605393) |
| Ensembl | [ENSG00000117139](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117139) |
| UniProt | [Q9UGL1](https://www.uniprot.org/uniprot/Q9UGL1) |
| Protein | Lysine-specific demethylase 5B |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), intellectual disability, autism spectrum disorder, [Parkinson's disease](/diseases/parkinsons-disease) |
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.
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 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: High expression in granule cells of the dentate gyrus and CA3 pyramidal neurons, regions critical for pattern separation and memory consolidation
- 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
¶ 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.
KDM5B has multiple connections to AD:
- Epigenetic aging: KDM5B expression increases with age in microglia, leading to excessive H3K4me3 removal at neuroprotective gene promoters including BDNF, NTRK2, and synaptic plasticity genes
- Tau pathology: KDM5B-mediated removal of H3K4me3 at the 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 and TYROBP, modulating microglial phagocytic capacity
- Dopaminergic vulnerability: KDM5B-mediated H3K4me3 removal at dopaminergic neuron survival genes (NURR1, PITX3) may contribute to selective vulnerability of substantia nigra neurons in PD
- 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 aggregates alter KDM5B nuclear localization, disrupting the H3K4me3 landscape in affected neurons
| 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) |
- 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 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
- KDM6B — JMJD3, H3K27 demethylase
- KDM1A — LSD1, H3K4 demethylase
- KDM4A — JMJD2A, H3K9/K36 demethylase
- SETD2 — H3K36 trimethyltransferase
- NSD1 — H3K36 dimethyltransferase
- BRD4 — Bromodomain reader of acetylated histones