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| Full Name | Lysine Demethylase 6B |
| Gene Symbol | KDM6B (JMJD3) |
| Chromosomal Location | 17p13.1 |
| NCBI Gene ID | [23135](https://www.ncbi.nlm.nih.gov/gene/23135) |
| OMIM | [611577](https://omim.org/entry/611577) |
| Ensembl | [ENSG00000132510](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000132510) |
| UniProt | [O15054](https://www.uniprot.org/uniprot/O15054) |
| Protein | Lysine-specific demethylase 6B / Jumonji domain-containing protein D3 |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), neuroinflammation |
NEUROD1 is a human gene. Variants in NEUROD1 have been implicated in Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
KDM6B (also known as JMJD3) encodes a Jumonji C (JmjC) domain-containing histone demethylase that specifically removes di- and trimethyl marks from histone H3 lysine 27 (H3K27me2/3). H3K27me3 is a key repressive histone mark deposited by Polycomb Repressive Complex 2 (PRC2), and its removal by KDM6B activates gene transcription. KDM6B thus functions as an epigenetic "switch" that opposes Polycomb-mediated silencing.
KDM6B plays critical roles in neural biology:
- Neuronal differentiation: KDM6B removes H3K27me3 from neurogenic gene promoters during the transition from neural stem cells to postmitotic neurons, activating expression of NEUROD1, TBR1, and other neuronal identity genes
- Microglial activation: KDM6B is a master epigenetic regulator of the microglial inflammatory response; it is rapidly upregulated by NF-κB signaling and demethylates H3K27me3 at pro-inflammatory gene loci including TNFα, IL-6, and IL-1β
- Macrophage polarization: KDM6B drives M1 (pro-inflammatory) macrophage/microglial polarization by activating inflammatory gene programs
- Aging epigenome: KDM6B expression increases with aging, contributing to the progressive loss of H3K27me3 that characterizes the aging epigenome and potentially derepressing deleterious gene programs
KDM6B requires Fe²⁺ and α-ketoglutarate as cofactors, linking its demethylase activity to cellular metabolic state and oxygen availability. Under hypoxic conditions, KDM6B activity is reduced, altering the epigenetic landscape of neurons.
KDM6B is significantly upregulated in AD brain, particularly in reactive microglia surrounding amyloid plaques. This upregulation drives several pathological processes:
- Neuroinflammatory amplification: KDM6B removes H3K27me3 from pro-inflammatory gene promoters (TNF, IL1B, IL6, complement components), converting microglia to a chronic inflammatory state that damages neurons
- Tau pathology: KDM6B activates kinase genes (CDK5, GSK3B) that hyperphosphorylate tau, promoting neurofibrillary tangle formation
- Amyloid processing: KDM6B demethylates the BACE1 promoter, increasing β-secretase expression and amyloidogenic APP processing
- Synaptic gene silencing: Paradoxically, KDM6B overactivity in glial cells can indirectly silence neuronal genes through inflammatory paracrine signaling
- Senescence: KDM6B activates the p16^INK4a/Rb senescence pathway by demethylating the CDKN2A locus, promoting cellular senescence in the aging brain
In PD, KDM6B contributes to dopaminergic neurodegeneration through:
- Activation of neuroinflammatory programs in nigral microglia
- Derepression of pro-apoptotic genes in stressed dopaminergic neurons
- Interaction with α-synuclein-driven inflammatory cascades — α-synuclein aggregates activate KDM6B through TLR2/4 signaling in microglia
- KDM6B-dependent epigenomic changes precede motor symptom onset in PD animal models
KDM6B upregulation in ALS spinal cord microglia drives neuroinflammation. KDM6B demethylates inflammatory gene promoters in activated microglia, amplifying the toxic environment surrounding motor neurons. TDP-43 pathology may further dysregulate KDM6B expression through altered RNA processing.
De novo mutations in KDM6B cause autosomal dominant intellectual disability (Stolerman syndrome). Affected individuals show developmental delay, behavioral abnormalities, and structural brain anomalies, underscoring KDM6B's essential role in neurodevelopment.
KDM6B shows distinct expression patterns across brain cell types:
- Microglia — Dramatically upregulated upon activation; KDM6B is one of the most strongly induced epigenetic regulators in the microglial inflammatory response
- Astrocytes — Moderate expression; increases with reactive astrogliosis
- Neurons — Expressed in differentiated neurons of cortex, hippocampus, and cerebellum; required for maintaining neuronal identity gene expression
- Oligodendrocyte precursors — KDM6B promotes oligodendrocyte differentiation and myelination programs
- Substantia nigra — Expressed in both neurons and glia; glial KDM6B upregulation precedes neuronal loss in PD models
KDM6B expression increases significantly with aging across all brain regions, correlating with the global loss of H3K27me3 observed in the aging brain.
¶ Common Variants and Risk Alleles
| Variant |
Type |
Association |
Effect |
| rs9916823 |
Regulatory |
AD-associated microglial activation |
Enhanced KDM6B expression |
| rs7216389 |
Intergenic (17q12-q21) |
Neuroinflammatory phenotype |
Modulates KDM6B regulation |
| p.R1276W |
Missense |
Stolerman syndrome (de novo) |
Impaired JmjC catalytic activity |
| p.Q1415* |
Nonsense |
Intellectual disability |
Loss of function |
- GSK-J4 (KDM6B inhibitor): The most studied KDM6B inhibitor; shows neuroprotective effects in AD and PD models by suppressing microglial neuroinflammation. GSK-J4 restores H3K27me3 at inflammatory gene loci and reduces pro-inflammatory cytokine production
- EPZ-6438 (EZH2 inhibitor): Paradoxically, EZH2 inhibition may compensate for KDM6B overactivity by reducing the H3K27me3 substrate pool, though this approach risks unintended gene derepression
- Anti-inflammatory epigenetic therapy: Combining KDM6B inhibition with HDAC inhibitors could rebalance the neuroinflammatory epigenome
- Cell-type-specific targeting: Microglia-targeted KDM6B inhibition (via CSF1R-antibody conjugates) could avoid disrupting beneficial KDM6B functions in neurons