TET3 (Tet Methylcytosine Dioxygenase 3) is the third member of the TET family of 5-methylcytosine hydroxylases and is uniquely expressed at high levels in the brain, particularly in neurons. While TET1 is primarily associated with embryonic stem cells and TET2 with hematopoietic cells, TET3 serves as the major TET enzyme in oocytes, zygotes, and post-mitotic neurons. TET3 catalyzes the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), which are key intermediates in active DNA demethylation. In neurons, TET3 regulates activity-dependent gene expression critical for synaptic plasticity, learning, and memory formation. Mutations in TET3 cause neurodevelopmental disorders, and TET3 dysfunction has been implicated in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
| Property |
Value |
| Gene Symbol |
TET3 |
| Full Name |
Tet Methylcytosine Dioxygenase 3 |
| Chromosomal Location |
2p13.1 |
| NCBI Gene ID |
200316 |
| OMIM |
617555 |
| Ensembl ID |
ENSG00000196950 |
| UniProt |
Q8IU60 |
| Protein Family |
TET family (Fe(II) and 2-oxoglutarate-dependent dioxygenases) |
| Length |
2,298 amino acids |
TET3, like other TET enzymes, requires Fe(II) and 2-oxoglutarate (2-OG) as cofactors to catalyze the hydroxylation of 5-methylcytosine:
- 5mC → 5hmC: First oxidation produces 5-hydroxymethylcytosine
- 5hmC → 5fC: Second oxidation produces 5-formylcytosine
- 5fC → 5caC: Third oxidation produces 5-carboxylcytosine
TET3 has the highest catalytic activity among the three TET enzymes and is the predominant 5mC hydroxylase in many tissues, particularly in the brain and during early development.
TET3 contains:
- N-terminal region: Low complexity region with potential regulatory functions
- C-terminal catalytic domain: Contains the Fe(II) binding site (HXD...H motif) and 2-OG binding motif (RxxxxD)
- DNA-binding capability: While lacking a CXXC domain, TET3 can associate with chromatin through protein interactions
TET3 has several distinctive features:
- Highest catalytic turnover: TET3 processes 5mC faster than TET1 or TET2
- Brain-enriched expression: Highest levels in neurons
- Activity-dependent regulation: Neuronal activity rapidly alters TET3 function
- Zygotic reprogramming: Critical for paternal genome demethylation after fertilization
TET3 is highly expressed in neurons throughout the brain:
- Cerebral cortex: Pyramidal neurons in layers 2-6
- Hippocampus: CA1, CA3, and dentate gyrus granule cells
- Cerebellum: Purkinje cells (highest expression in the brain)
- Amygdala: Various nuclei
- Thalamus: Relay neurons
TET3 plays a crucial role in neuronal activity-dependent transcription:
- Synaptic activity: Neuronal stimulation triggers calcium influx
- TET3 recruitment: Activity-dependent signaling recruits TET3 to immediate-early genes
- 5hmC deposition: TET3 generates 5hmC at promoter and enhancer regions
- Demethylation: 5hmC leads to active DNA demethylation
- Transcription activation: Demethylation enables transcription factor binding
TET3 regulates genes critical for synaptic plasticity:
- Immediate-early genes: c-Fos, Arc, Egr1
- Synaptic proteins: Synapsin, PSD-95
- Receptors: NMDA and AMPA receptor subunits
- Activity-dependent modifications: Long-term potentiation and depression
¶ Learning and Memory
TET3 is essential for learning and memory:
- Hippocampal learning: TET3 required for spatial memory formation
- Cortical plasticity: TET3 in motor cortex learning
- Memory consolidation: Activity-dependent TET3 function during sleep
- Aging: TET3 dysfunction contributes to age-related cognitive decline
TET3 alterations are prominent in AD:
- 5hmC changes: Altered 5hmC patterns in AD hippocampus and cortex
- Amyloid metabolism: TET3 regulates genes involved in APP processing
- Tau pathology: TET3 dysfunction affects tau phosphorylation pathways
- Synaptic plasticity: Activity-dependent gene dysregulation
- Neuroinflammation: TET3 in microglial inflammatory responses
In PD, TET3 is implicated through:
- Dopaminergic neurons: TET3 expression in substantia nigra
- Mitochondrial function: TET3 regulation of mitochondrial genes
- Oxidative stress: TET3 response to oxidative damage
- Alpha-synuclein: TET3 alterations affect protein clearance
TET3 in ALS:
- Motor neurons: TET3 expression in spinal motor neurons
- Mitochondrial dysfunction: Altered TET3 in ALS models
- Epigenetic changes: Global 5hmC alterations in ALS tissue
- Neuroinflammation: TET3-microglia interactions
TET3 mutations cause autosomal dominant neurodevelopmental disorders:
- Intellectual disability: De novo missense mutations
- Speech impairment: Language development delays
- Facial dysmorphism: Characteristic features
- Developmental delay: Variable severity
- Autism spectrum: Some patients meet ASD criteria
TET3 is involved in Angelman syndrome pathogenesis:
- UBE3A-ATS locus: TET3 regulates methylation at this imprinted region
- Maternal allele expression: TET3 affects paternal UBE3A-ATS transcription
- Therapeutic implications: Targeting TET3 as potential treatment
5hmC shows distinct regional and cell-type patterns:
- Neuronal enrichment: Higher in neurons than glia
- Regional variation: Highest in cortex and hippocampus
- Gene body accumulation: 5hmC enriched in gene bodies of actively transcribed genes
- Developmental changes: Dynamic patterns during development and aging
Beyond demethylation intermediate, 5hmC functions as:
- Stable epigenetic mark: Can be maintained through cell division
- Transcription regulation: Distinct from 5mC effects
- Brain-specific: Particularly abundant in brain
- Disease marker: Changes in 5hmC patterns reflect disease state
TET enzymes are attractive therapeutic targets:
- TET activators: Vitamin C, 2-OG derivatives enhance TET activity
- Gene therapy: Viral delivery of functional TET3
- Small molecule modulators: Synthetic TET3-targeting compounds
- Vitamin C supplementation: Increases TET activity
- Activity-dependent therapy: Enhance neuronal activity to recruit TET3
- Combination approaches: TET activation with other interventions
- Early intervention: Target TET3 during critical periods
- Gene therapy: For specific TET3 mutations
- Epigenetic drugs: Modulate DNA methylation dynamically
TET3 expression is tightly regulated:
- Oocytes: Very high maternal expression
- Zygotes: Paternal genome demethylation
- Embryogenesis: Decreasing through development
- Adult brain: Maintained in neurons
- Brain: Highest expression in neurons
- Oocytes/Embryos: Maternal contribution
- Liver: Lower expression
- Other tissues: Minimal expression
¶ Interactions and Pathways
TET3 interacts with:
- O-GlcNAc transferase (OGT): Targeting to chromatin
- Transcription factors: Activity-dependent recruitment
- DNA repair proteins: Base excision repair pathway
- Chromatin remodelers: Facilitating demethylation
- Calcium signaling: Activity-dependent TET3 regulation
- cAMP/PKA pathway: Modulates TET3 function
- MAPK signaling: Activity-dependent gene regulation
- Metabolic sensing: 2-OG availability affects TET3 activity
- 5hmC levels: In brain tissue, CSF
- TET3 expression: Peripheral blood mononuclear cells
- Genetic testing: For neurodevelopmental disorders
- Missense mutations: Cause neurodevelopmental disorders
- Common variants: May influence neurodegenerative disease risk
- Somatic mutations: Some cancers harbor TET3 mutations
Current research focuses on:
- TET3-specific small molecule modulators
- Understanding TET3 in specific brain circuits
- TET3 gene therapy approaches
- Biomarker development
In cortex:
- Highest TET3 expression in brain
- Neuronal activity regulation
- Learning and memory
- Plasticity mechanisms
In hippocampus:
- Dentate gyrus neural stem cells
- CA1 and CA3 neurons
- Memory formation
- Adult neurogenesis
In cerebellum:
- Purkinje cells
- Motor learning
- Coordination functions
In substantia nigra:
- Dopaminergic neurons
- PD relevance
- Vulnerability mechanisms
¶ TET3 and Protein Aggregation
In AD:
- 5hmC changes in AD brain
- Neuronal activity dysregulation
- Epigenetic mechanisms
In tauopathies:
- 5hmC at tau-related genes
- Epigenetic changes
In PD:
- Epigenetic regulation
- Vulnerability mechanisms
- Inflammatory gene regulation
- Activation states
- Not well characterized
- Metabolic functions
- Not primary focus
- Myelination genes
- Not well studied
¶ TET3 and Synaptic Function
- Neuronal activation: Triggers TET3 recruitment
- Gene expression: Activity-dependent genes
- Synaptic plasticity: Learning mechanisms
- Memory formation: Epigenetic basis
- Epigenetic dysregulation
- Not well characterized
- Tet3 knockout: Developmental defects
- Conditional: Brain-specific
- Neurodevelopmental issues
- Learning deficits
¶ TET3 and Cellular Stress
- 5hmC changes under stress
- Not well studied
- Alpha-ketoglutarate relationships
- Not primary focus
- Developmental disorder testing
- Not routine for neurodegeneration
- 5hmC levels
- Not well validated
| Approach |
Status |
Indication |
| Vitamin C |
Preclinical |
TET activation |
| Gene therapy |
Research |
Developmental |
- TAB-seq
- BS-seq
- Single-cell approaches