KDM2B

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KDM2B

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">KDM2B</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Lysine Demethylase 2B</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KDM2B</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>FBXL10, JHDM1B, NDY1, PCCX2</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>12q24.31</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[609078](https://omim.org/entry/609078)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q8NHM5](https://www.uniprot.org/uniprot/Q8NHM5)</td>
</tr>
<tr>
<td class="label">HGNC</td>
<td>[13610](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:13610)</td>
</tr>
<tr>
<td class="label">Entrez Gene</td>
<td>[84678](https://www.ncbi.nlm.nih.gov/gene/84678)</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>[ENSG00000089094](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000089094)</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs12304921</td>
<td>Intronic SNP</td>
</tr>
<tr>
<td class="label">p.R242Q</td>
<td>Missense (JmjC)</td>
</tr>
<tr>
<td class="label">p.C573Y</td>
<td>Missense (CXXC)</td>
</tr>
<tr>
<td class="label">12q24.31 microdeletion</td>
<td>CNV</td>
</tr>
<tr>
<td class="label">Associate

...

KDM2B

KDM2B

</div>

Overview

Mermaid diagram (expand to render)

KDM2B is a human gene. Variants in KDM2B have been implicated in Alzheimer's Disease, Parkinson's Disease, Neurodevelopmental Disorders. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

KDM2B (Lysine Demethylase 2B), also known as FBXL10 or JHDM1B, encodes a JmjC domain-containing histone demethylase that removes mono- and dimethyl marks from histone H3 lysine 36 (H3K36me1/2). KDM2B serves a dual function as both a chromatin modifier and a component of variant Polycomb Repressive Complex 1 (vPRC1.1), where it recruits the complex to unmethylated CpG islands through its CXXC zinc finger domain.[1] In the nervous system, KDM2B is essential for neural progenitor maintenance, transcriptional regulation at bivalent promoters, and prevention of aberrant gene activation. Dysregulated KDM2B activity has been implicated in neurodevelopmental disorders and age-related neurodegeneration including [Alzheimer's disease](/diseases/alzheimers-disease).

Function and Mechanism

KDM2B contains multiple functional domains: an N-terminal JmjC demethylase domain, a CXXC zinc finger (CpG-binding), a PHD finger, an F-box domain, and leucine-rich repeats. This domain architecture enables KDM2B to integrate chromatin reading, writing, and Polycomb recruitment functions.

H3K36me1/2 Demethylation

The JmjC domain of KDM2B catalyzes Fe(II)- and 2-oxoglutarate-dependent oxidative demethylation of H3K36me1 and H3K36me2, but not H3K36me3. H3K36me2 is an active transcription mark deposited by [NSD1](/genes/nsd1), [NSD2](/genes/nsd2), and [NSD3](/genes/nsd3). By removing H3K36me2 at CpG island promoters, KDM2B maintains a chromatin environment permissive for Polycomb-mediated repression, since H3K36 methylation antagonizes PRC2-mediated H3K27me3 deposition.[1]

Variant PRC1.1 Recruitment

KDM2B is the defining subunit of variant PRC1.1 (vPRC1.1), where it heterodimerizes with PCGF1 and recruits the complex to unmethylated CpG islands via its CXXC domain. This CpG-dependent recruitment mechanism is independent of H3K27me3 reading by CBX proteins, distinguishing vPRC1.1 from canonical PRC1. The vPRC1.1 complex includes [RNF2](/genes/rnf2) (RING1B), PCGF1, BCOR, and USP7, and deposits H2AK119ub1 to initiate de novo Polycomb domain formation.[2]

Bivalent Chromatin Regulation

At bivalent promoters — those carrying both activating H3K4me3 and repressive H3K27me3 — KDM2B maintains the repressive component by removing H3K36me2 that would otherwise antagonize PRC2 activity. This is critical in neural progenitors where bivalent domains poise developmental genes for rapid activation upon differentiation signals.[3]

Ribosomal RNA Gene Silencing

KDM2B also localizes to nucleoli where it represses ribosomal RNA (rRNA) gene transcription by demethylating H3K36me2 at rDNA repeats. This function connects KDM2B to nucleolar stress responses and protein synthesis regulation, processes disrupted in neurodegenerative conditions.[4]

Disease Associations

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), KDM2B expression declines in aging hippocampal [neurons](/entities/neurons), leading to accumulation of H3K36me2 at Polycomb target genes. This erodes Polycomb-mediated silencing, causing inappropriate reactivation of developmental transcription factors and cell cycle genes that drive neuronal dysfunction. Loss of KDM2B-mediated vPRC1.1 recruitment disrupts the CpG island-dependent Polycomb targeting that maintains neuronal identity.[5]

Parkinson's Disease

Reduced KDM2B function in dopaminergic neurons contributes to dysregulation of Polycomb target genes involved in neuronal survival. The intersection of KDM2B-dependent H3K36me2 regulation with [alpha-synuclein](/proteins/alpha-synuclein)-induced transcriptional perturbation creates a synergistic vulnerability in substantia nigra neurons.[6]

Neurodevelopmental Disorders

De novo heterozygous variants in KDM2B have been identified in patients with intellectual disability, microcephaly, and corpus callosum abnormalities. These variants typically affect the JmjC catalytic domain or the CXXC zinc finger, disrupting demethylase activity or CpG island targeting, respectively. KDM2B haploinsufficiency impairs neural progenitor self-renewal and premature differentiation.[7]

Expression in the Nervous System

KDM2B is broadly expressed throughout the brain, with highest levels in the [hippocampus](/brain-regions/hippocampus), cerebral [cortex](/brain-regions/cortex), and cerebellum. In the developing brain, KDM2B is enriched in neural progenitor zones (ventricular and subventricular zones) where it maintains Polycomb-mediated repression of lineage-inappropriate genes. Expression declines with aging, particularly in the hippocampal CA1 region and [entorhinal cortex](/brain-regions/entorhinal-cortex) — regions most vulnerable in AD.[5]

At the cellular level, KDM2B is expressed in neurons, oligodendrocyte precursors, and neural stem cells. Microglial expression is lower but upregulated during inflammatory activation, where KDM2B modulates inflammatory gene transcription through H3K36me2 regulation.[6]

Common Variants

Therapeutic Implications

KDM2B presents both challenges and opportunities as a therapeutic target. Enhancing KDM2B activity could restore Polycomb-mediated gene silencing in aging neurons and delay neurodegeneration. However, KDM2B overexpression promotes tumorigenesis through excessive silencing of tumor suppressor genes. Small molecules that selectively enhance KDM2B catalytic activity without affecting its PRC1.1 scaffolding function, or that stabilize KDM2B protein in post-mitotic neurons, represent potential therapeutic strategies.[8]

The connection between KDM2B and vPRC1.1 suggests that targeting the broader Polycomb pathway — for instance with [EED](/genes/eed) stabilizers or [BMI1](/genes/bmi1) activators — could compensate for age-related KDM2B decline. Conversely, inhibition of H3K36 methyltransferases like [NSD1](/genes/nsd1)/[NSD2](/genes/nsd2) could phenocopy KDM2B activity by reducing H3K36me2 substrate levels.[3]

External Links

[OMIM: 609078](https://omim.org/entry/609078)
[GeneCards: KDM2B](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDM2B)
[UniProt: Q8NHM5](https://www.uniprot.org/uniprot/Q8NHM5)
[Allen Brain Atlas: KDM2B](https://portal.brain-map.org/search?query=KDM2B)
[GTEx Portal: KDM2B](https://gtexportal.org/home/gene/KDM2B)

References

[He et al., The H3K36 demethylase Jhdm1b/Kdm2b regulates cell fate through noncanonical PRC1 (2013) (2013)](https://doi.org/10.1016/j.molcel.2013.01.002)

[Farcas et al., KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands (2012) (2012)](https://doi.org/10.7554/eLife.00205)

[Blackledge et al., Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation (2014) (2014)](https://doi.org/10.1016/j.cell.2014.05.004)

[Frescas et al., JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes (2007) (2007)](https://doi.org/10.1038/nature06255)

[von Schimmelmann et al., Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration (2016) (2016)](https://doi.org/10.1038/nn.4360)

[Unknown, Basavarajappa & Bhatt, Epigenetic mechanisms in neurological and neurodegenerative diseases (2021) (2021)](https://doi.org/10.3389/fgene.2021.747927)

[Unknown, Deciphering Developmental Disorders Study, Prevalence and architecture of de novo mutations in developmental disorders (2017) (2017)](https://doi.org/10.1038/nature21062)

[Boulard et al., FBXL10 protects Polycomb-bound genes from hypermethylation (2015) (2015)](https://doi.org/10.1038/ng.3272)

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KDM2B

KDM2B

KDM2B

Overview

Function and Mechanism

H3K36me1/2 Demethylation

Variant PRC1.1 Recruitment

Bivalent Chromatin Regulation

Ribosomal RNA Gene Silencing

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Neurodevelopmental Disorders

Expression in the Nervous System

Common Variants

Therapeutic Implications

See Also

External Links

References