KDM6B (JMJD3)
<div class="infobox infobox-gene">
<h3>KDM6B</h3>
<table> [@das2017]
<tr><td><strong>Full Name</strong></td><td>Lysine Demethylase 6B</td></tr> [@kruidenier2012]
<tr><td><strong>Gene Symbol</strong></td><td>KDM6B (JMJD3)</td></tr> [@burgold2012]
<tr><td><strong>Chromosomal Location</strong></td><td>17p13.1</td></tr> [@agger2007]
<tr><td><strong>NCBI Gene ID</strong></td><td>[23135](https://www.ncbi.nlm.nih.gov/gene/23135)</td></tr> [@przanowski2014]
<tr><td><strong>OMIM</strong></td><td>[611577](https://omim.org/entry/611577)</td></tr> [@stolerman2019]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000132510](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000132510)</td></tr> [@brehm2015]
<tr><td><strong>UniProt</strong></td><td>[O15054](https://www.uniprot.org/uniprot/O15054)</td></tr> [@nativio2018]
<tr><td><strong>Protein</strong></td><td>Lysine-specific demethylase 6B / Jumonji domain-containing protein D3</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), neuroinflammation</td></tr>
</table>
</div>
Overview
Mermaid diagram (expand to render)
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.
Gene Function
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)](/genes/ezh2), 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](/entities/neurons), activating expression of [NEUROD1](/genes/neurod1), [TBR1](/genes/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](/entities/nf-kb) signaling and demethylates H3K27me3 at pro-inflammatory gene loci including [TNFα](/genes/tnf), [IL-6](/genes/il6), and [IL-1β](/genes/il1b)
- 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.
Disease Associations
Alzheimer's Disease
KDM6B is significantly upregulated in [AD](/diseases/alzheimers-disease) brain, particularly in reactive [microglia](/cell-types/microglia-neuroinflammation) surrounding amyloid plaques. This upregulation drives several pathological processes:
- Neuroinflammatory amplification: KDM6B removes H3K27me3 from pro-inflammatory gene promoters ([TNF](/genes/tnf), [IL1B](/genes/il1b), [IL6](/genes/il6), complement components), converting microglia to a chronic inflammatory state that damages neurons
- [Tau](/proteins/tau) pathology: KDM6B activates kinase genes ([CDK5](/genes/cdk5), [GSK3B](/genes/gsk3b)) that hyperphosphorylate [tau](/genes/mapt), promoting neurofibrillary tangle formation
- Amyloid processing: KDM6B demethylates the [BACE1](/genes/bace1) promoter, increasing [β-secretase](/entities/bace1) expression and amyloidogenic [APP](/genes/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
Parkinson's Disease
In [PD](/diseases/parkinsons-disease), 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](/entities/snca)-driven inflammatory cascades — [α-synuclein](/proteins/alpha-synuclein) aggregates activate KDM6B through TLR2/4 signaling in microglia
- KDM6B-dependent epigenomic changes precede motor symptom onset in PD animal models
Amyotrophic Lateral Sclerosis
KDM6B upregulation in [ALS](/diseases/amyotrophic-lateral-sclerosis) spinal cord microglia drives neuroinflammation. KDM6B demethylates inflammatory gene promoters in activated microglia, amplifying the toxic environment surrounding motor neurons. [TDP-43](/genes/tardbp) pathology may further dysregulate KDM6B expression through altered RNA processing.
Neurodevelopmental Disorders
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.
Expression Profile
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](/entities/astrocytes) — Moderate expression; increases with reactive astrogliosis
- Neurons — Expressed in differentiated neurons of [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/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 |
Therapeutic Implications
- 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](/genes/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](/genes/hdac1) 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
See Also
- [EZH2](/genes/ezh2) — Deposits H3K27me3 marks removed by KDM6B
- [KDM5A](/genes/kdm5a) — H3K4 demethylase, related epigenetic regulator
- [KDM1A](/genes/kdm1a) — LSD1, H3K4/K9 demethylase
- [Chromatin Remodeling in Neurodegeneration](/mechanisms/chromatin-remodeling)
- [TREM2](/genes/trem2) — Microglial receptor, inflammatory signaling
External Links
- [NCBI Gene: KDM6B](https://www.ncbi.nlm.nih.gov/gene/23135)
- [GeneCards: KDM6B](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDM6B)
- [Allen Brain Atlas: KDM6B](https://human.brain-map.org/microarray/search/show?search_term=KDM6B)
- [OMIM: 611577](https://omim.org/entry/611577)
References
[Wijayatunge et al., The histone demethylase Kdm6b regulates subtype diversification of mouse spinal motor neurons during development (2014) (2014)](https://doi.org/10.1038/ncomms5064)
[Tang et al., Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson's disease (2014) (2014)](https://doi.org/10.1038/cdd.2013.159)
[Das et al., Bhatt & coworkers, KDM6B in neuroinflammatory signaling (2017) (2017)](https://doi.org/10.1016/j.bbi.2017.04.013)
[Kruidenier et al., A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response (2012) (2012)](https://doi.org/10.1038/nature11262)
[Burgold et al., The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival (2012) (2012)](https://doi.org/10.1016/j.celrep.2012.09.013)
[Agger et al., UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development (2007) (2007)](https://doi.org/10.1038/nature06145)
[Przanowski et al., The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia (2014) (2014)](https://doi.org/10.1186/1742-2094-11-15)
[Stolerman et al., Genetic variants in KDM6B associated with neurodevelopmental disability (2019) (2019)](https://doi.org/10.1002/ajmg.a.61107)
[Brehm et al., Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production (2015) (2015)](https://doi.org/10.1172/JCI81260)
[Nativio et al., Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease (2018) (2018)](https://doi.org/10.1038/s41593-018-0101-9)Pathway Diagram
The following diagram shows the key molecular relationships involving KDM6B (JMJD3) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)