RNF2
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">RNF2</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ring Finger Protein 2</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>RNF2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>RING1B, RING2, BAP-1, DINF</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q25.3</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[608985](https://omim.org/entry/608985)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q99496](https://www.uniprot.org/uniprot/Q99496)</td>
</tr>
<tr>
<td class="label">HGNC</td>
<td>[10061](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10061)</td>
</tr>
<tr>
<td class="label">Entrez Gene</td>
<td>[6045](https://www.ncbi.nlm.nih.gov/gene/6045)</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>[ENSG00000121481](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000121481)</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs199502155</td>
<td>Missense (R338Q)</td>
</tr>
<tr>
<td class="label">RNF2 haploinsufficiency</td>
<td>Copy number loss</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">17 edges</a></td>
</tr>
</table>
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RNF2
</div>
Overview
Mermaid diagram (expand to render)
RNF2 is a human gene. Variants in RNF2 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.
RNF2 (Ring Finger Protein 2), also known as RING1B, encodes the catalytic E3 ubiquitin ligase subunit of Polycomb Repressive Complex 1 (PRC1). RNF2 monoubiquitinates histone H2A at lysine 119 (H2AK119ub1), a modification central to Polycomb-mediated gene silencing.<sup>[1]</sup> In the nervous system, RNF2 is essential for neural stem cell differentiation, maintenance of neuronal identity, and repression of non-neuronal gene programs. Dysregulation of RNF2-mediated H2AK119ub1 has been implicated in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and neurodevelopmental disorders.
Function and Mechanism
RNF2 contains an N-terminal RING domain that catalyzes the transfer of ubiquitin from E2 conjugating enzymes (primarily UBE2D/UBCH5 family) to H2AK119. Its catalytic activity is dramatically enhanced (approximately 10-fold) through heterodimerization with [BMI1](/genes/bmi1) (PCGF4) or other PCGF paralogs via their respective RING domains.<sup>[1]</sup>
Canonical PRC1 and Gene Silencing
In canonical PRC1 (cPRC1), RNF2-BMI1 associates with CBX chromodomain proteins (CBX2/4/6/7/8) and PHC (polyhomeotic) subunits. CBX proteins read H3K27me3 marks deposited by PRC2, recruiting RNF2-BMI1 to PRC2-target genes. H2AK119ub1 then reinforces transcriptional silencing by blocking RNA Polymerase II elongation, compacting chromatin, and recruiting additional PRC complexes.<sup>[2]</sup>
Variant PRC1 Complexes
RNF2 also participates in variant PRC1 (vPRC1) complexes, where it pairs with PCGF1, PCGF2, PCGF3, PCGF5, or PCGF6 instead of BMI1/PCGF4. Variant PRC1 complexes containing RYBP or YAF2 are recruited to chromatin independently of H3K27me3 and deposit H2AK119ub1 at distinct genomic targets, including CpG islands, establishing a PRC2-independent silencing pathway.<sup>[3]</sup>
Neuronal Gene Regulation
During neural differentiation, RNF2 represses pluripotency genes and non-neuronal lineage determinants, ensuring proper neuronal identity. In postmitotic [neurons](/entities/neurons), RNF2 maintains silencing of cell cycle genes and alternative lineage programs. Conditional deletion of Ring1b in mouse forebrain neurons leads to derepression of non-neuronal genes and progressive neurodegeneration.<sup>[4]</sup>
Chromatin Compaction
Beyond its catalytic function, RNF2 contributes to chromatin compaction through H2AK119ub1-independent mechanisms. PRC1 complexes containing RNF2 can bridge nucleosomes and compact chromatin fibers, contributing to long-range gene silencing at Polycomb domains.<sup>[5]</sup>
Disease Associations
Alzheimer's Disease
In [Alzheimer's disease](/diseases/alzheimers-disease), H2AK119ub1 levels are globally reduced in affected cortical regions, consistent with impaired RNF2-[BMI1](/genes/bmi1) function. Loss of H2AK119ub1 at [BACE1](/genes/bace1) regulatory regions correlates with increased [beta-secretase](/entities/bace1) expression and [amyloid-beta](/proteins/amyloid-beta) production. RNF2 dysfunction also permits derepression of inflammatory genes normally silenced by PRC1 in [microglia](/cell-types/microglia-neuroinflammation).<sup>[6]</sup>
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), dopaminergic neurons of the substantia nigra show reduced RNF2 occupancy at cell cycle gene promoters, potentially contributing to aberrant cell cycle re-entry and neuronal death. RNF2-mediated gene silencing is disrupted by [alpha-synuclein](/proteins/alpha-synuclein) aggregation, which sequesters PRC1 components away from chromatin.<sup>[7]</sup>
Neurodevelopmental Disorders
Heterozygous loss-of-function mutations in RNF2 cause a neurodevelopmental syndrome characterized by intellectual disability, seizures, and variable dysmorphic features, underscoring the gene's critical role in brain development.<sup>[8]</sup>
Huntington's Disease
Mutant [huntingtin](/proteins/huntingtin) protein disrupts PRC1 chromatin targeting in striatal neurons, leading to altered RNF2 occupancy and derepression of non-neuronal genes. This contributes to the loss of striatal neuronal identity characteristic of [Huntington's disease](/diseases/huntington-disease).<sup>[9]</sup>
Expression
RNF2 is ubiquitously expressed but shows enrichment in the central nervous system, particularly in neural progenitor cells, cortical neurons, hippocampal pyramidal neurons, and cerebellar Purkinje cells. Expression is highest during embryonic neurogenesis and remains at moderate levels in the adult brain. In microglia, RNF2 helps maintain the homeostatic transcriptional state by silencing inflammatory gene programs.
Common Variants
Therapeutic Implications
- PRC1 activators: Small molecules enhancing RNF2-BMI1 interaction or catalytic activity could restore H2AK119ub1 levels in neurodegeneration
- Targeted protein degradation: PROTACs targeting non-neuronal gene products derepressed by RNF2 loss
- Gene therapy: AAV-mediated RNF2 supplementation in vulnerable neuronal populations
- Downstream targets: Directly inhibiting aberrantly derepressed targets (e.g., BACE1) as alternative to restoring RNF2 function
See Also
- [BMI1](/genes/bmi1) — PRC1 RING domain cofactor](/genes)
- [EED](/genes/eed) — PRC2 core subunit](/genes)
- [SUZ12](/genes/suz12) — PRC2 core subunit](/genes)
- [JARID2](/genes/jarid2) — PRC2 accessory subunit](/genes)
- [EZH2](/genes/ezh2) — PRC2 catalytic subunit](/genes)
- [CBX5](/genes/cbx5) — Heterochromatin reader
External Links
- [NCBI Gene: RNF2](https://www.ncbi.nlm.nih.gov/gene/6045)](/genes/rnf2)
- [UniProt: Q99496](https://www.uniprot.org/uniprot/Q99496)
- [GeneCards: RNF2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=RNF2)
References
[Wang et al., Role of histone H2A ubiquitination in Polycomb silencing (2004) (2004)](https://doi.org/10.1038/nature02985)
[Gao et al., PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes (2012) (2012)](https://doi.org/10.1016/j.molcel.2012.01.002)
[Tavares et al., RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3 (2012) (2012)](https://doi.org/10.1016/j.cell.2012.02.029)
[Hirabayashi et al., Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition (2009) (2009)](https://doi.org/10.1016/j.neuron.2009.08.021)
[Francis et al., Chromatin compaction by a polycomb group protein complex (2004) (2004)](https://doi.org/10.1126/science.1091163)
[Flamier et al., Modeling late-onset sporadic Alzheimer's disease through BMI1 deficiency (2018) (2018)](https://doi.org/10.1038/s41467-018-06899-y)
[Chatoo et al., The polycomb group gene Bmi1 regulates antioxidant defenses in neurons (2009) (2009)](https://doi.org/10.1073/pnas.0904529106)
[Turnpenny et al., Missense mutations in RNF2 define a neurodevelopmental syndrome (2018) (2018)](https://doi.org/10.1038/s41436-018-0067-9)
[von Schimmelmann et al., Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration (2016) (2016)](https://doi.org/10.1038/nn.4360)
[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)Pathway Diagram
The following diagram shows the key molecular relationships involving RNF2 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)