DNMT3B (DNA Methyltransferase 3 Beta) is a de novo DNA methyltransferase responsible for establishing [DNA methylation](/entities/dna-methylation) patterns during development and in differentiated cells. In the nervous system, DNMT3B plays important roles in epigenetic regulation of gene expression, neural development, and may be implicated in neurodegenerative disease pathogenesis.
Dnmt3B Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
DNMT3B (DNA Methyltransferase 3 Beta) is a de novo DNA methyltransferase responsible for establishing [DNA methylation](/entities/dna-methylation) patterns during development and in differentiated cells. In the nervous system, DNMT3B plays important roles in epigenetic regulation of gene expression, neural development, and may be implicated in neurodegenerative disease pathogenesis.
Dnmt3B Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">DNA Methyltransferase 3 Beta</th></tr>
<tr><td><strong>Protein Name</strong></td><td>DNA Methyltransferase 3 Beta</td></tr>
<tr><td><strong>Gene</strong></td><td>[DNMT3B](/genes/dnmt3b)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9U5U1](https://www.uniprot.org/uniprot/Q9U5U1)</td></tr>
<tr><td><strong>Protein Length</strong></td><td>853 amino acids</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~96 kDa</td></tr>
<tr><td><strong>Subcellular Location</strong></td><td>Nucleus</td></tr>
<tr><td><strong>Protein Family</strong></td><td>DNMT3 family</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>5YXU, 6FR9</td></tr>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autism" style="color:#ef9a9a">Autism</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">24 edges</a></td>
</tr>
</table>
</div>
DNA Methyltransferase 3 Beta (DNMT3B) is a de novo DNA methyltransferase that catalyzes the addition of methyl groups to cytosine residues in CpG dinucleotides. Unlike DNMT1, which maintains existing methylation patterns during DNA replication, DNMT3B establishes de novo methylation patterns during embryonic development and cellular differentiation. In the nervous system, DNMT3B plays critical roles in brain development, neuronal differentiation, synaptic plasticity, and cognitive function. Dysregulation of DNMT3B activity has been implicated in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as neurodevelopmental disorders.
DNMT3B contains several key structural domains that mediate its catalytic activity and protein-protein interactions. The N-terminal regulatory domain includes a PWWP domain that binds to histone H3 tails modified with H3K36me3, targeting DNMT3B to methylated gene bodies. A ADD (ATRX-DNMT3-DNMT3L) domain at the C-terminus of the N-terminal region mediates interactions with unmodified histone H3 tails and recruits DNMT3B to heterochromatic regions. The C-terminal catalytic domain contains conserved motifs characteristic of DNA methyltransferases, including the S-adenosyl-L-methionine (SAM) binding pocket and the catalytic loop that contacts target cytosine residues in DNA. The catalytic domain shares homology with other eukaryotic DNA methyltransferases and requires tetramerization for full activity.
In the central nervous system, DNMT3B is highly expressed during embryonic development and early postnatal stages, where it establishes DNA methylation patterns essential for neurogenesis and neuronal differentiation. During cortical development, DNMT3B-mediated de novo methylation silences progenitor-specific genes while activating neuron-specific genes, facilitating the transition from neural progenitor cells to post-mitotic [neurons](/entities/neurons). In adult brain, DNMT3B expression is maintained at lower levels in neural stem cells of the subventricular zone and dentate gyrus, where it continues to play roles in adult neurogenesis and hippocampal plasticity. DNMT3B also contributes to synaptic plasticity by regulating methylation of genes involved in synaptic function, learning, and memory. Animal models with DNMT3B knockout exhibit severe developmental defects and embryonic lethality, underscoring its essential role in development.
In Alzheimer's disease (AD), alterations in DNMT3B expression and activity have been documented in postmortem brain tissue. Studies have shown decreased DNMT3B protein levels in the [hippocampus](/brain-regions/hippocampus) and prefrontal [cortex](/brain-regions/cortex) of AD patients compared to age-matched controls. This reduction in DNMT3B correlates with global DNA hypomethylation observed in AD brain, particularly at genes involved in synaptic function, energy metabolism, and inflammation. The hypomethylation may result from reduced DNMT3B activity, increased DNA demethylation (via TET enzymes), or combination of both. Notably, genes encoding [amyloid precursor protein](/entities/app-protein) (APP) and [tau](/proteins/tau) (MAPT) show altered methylation patterns in AD, potentially affecting their expression. Conversely, some genomic regions display hypermethylation in AD, including genes involved in DNA repair and mitochondrial function, which may contribute to cellular vulnerability.
DNA methylation alterations have also been reported in Parkinson's disease (PD) brain and blood. Studies on postmortem substantia nigra tissue have identified differentially methylated regions (DMRs) associated with PD pathogenesis, including genes involved in mitochondrial function (PARK2/PARKIN), protein quality control (SNCA), and neuroinflammation. While DNMT3B's specific role in PD is less characterized than in AD, evidence suggests that epigenetic dysregulation contributes to PD pathogenesis. Interestingly, environmental factors associated with PD risk, such as pesticide exposure, can alter DNA methylation patterns through effects on DNMT enzymes. The interaction between genetic susceptibility (e.g., LRRK2, GBA mutations) and epigenetic modifications in PD remains an active area of investigation.
Huntington's disease (HD) involves progressive degeneration of striatal and cortical neurons due to mutant [huntingtin](/proteins/huntingtin-protein) (mHTT) protein expansion. DNA methylation changes have been identified in HD brain, including altered patterns at genes regulating neuronal survival and function. DNMT3B may contribute to these alterations through direct interaction with mutant [huntingtin protein](/proteins/huntingtin-protein), which can sequester transcriptional regulators and epigenetic modifiers. Studies have shown that mHTT can bind to epigenetic regulators including DNMTs, potentially disrupting normal DNA methylation patterns. The epigenetic changes in HD may amplify transcriptional dysregulation already caused by mutant [huntingtin](/proteins/huntingtin)'s effects on transcription factors and co-activators.
DNMT3B dysregulation has been implicated in other neurodegenerative and neurodevelopmental conditions. In amyotrophic lateral sclerosis (ALS), altered DNA methylation patterns have been identified in motor cortex and blood, with some studies reporting changes at specific loci associated with disease susceptibility. In frontotemporal dementia (FTD), particularly the [C9orf72](/entities/c9orf72) expansion form, DNA methylation at the repeat expansion site can influence disease expression. The DNMT3 family, including DNMT3B, may contribute to the epigenetic regulation of these disease-related genes. Additionally, DNMT3B mutations cause Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome, a rare disorder that includes neurodegeneration-like features, highlighting the importance of proper DNA methylation for neurological function.
Epigenetic therapy targeting DNA methyltransferases represents a potential approach for neurodegenerative diseases. However, DNMT3B presents both opportunities and challenges as a therapeutic target:
Key areas of ongoing research include:
The study of Dnmt3B Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
<sup>[1]</sup> Feng J, et al. (2010). Dnmt1 and Dnmt3a maintain DNA methylation and neuronal function in the forebrain. Nature Neuroscience 13(4):423-430. PMID: 20308989(https://pubmed.ncbi.nlm.nih.gov/20308989/)
<sup>[2]</sup> Wu H, et al. (2010). Dnmt3a-dependent non-CpG methylation regulates neuronal gene expression. Science 326(5957):1514. PMID: 21048107(https://pubmed.ncbi.nlm.nih.gov/21048107/)
<sup>[3]</sup> Chen T, et al. (2002). Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells. Cell 111(4):477-487. PMID: 12437923(https://pubmed.ncbi.nlm.nih.gov/12437923/)
<sup>[4]</sup> Mellen M, et al. (2017). MeCP2 reinforces neuronal gene expression by enhancing chromatin accessibility. Nature Neuroscience 20(11):1592-1603. PMID: 28920935(https://pubmed.ncbi.nlm.nih.gov/28920935/)
<sup>[5]</sup> Sahpazidou D, et al. (2014). Global DNA methylation in cortical samples from patients with Alzheimer's disease. Current Alzheimer Research 11(3):251-258. PMID: 24499732(https://pubmed.ncbi.nlm.nih.gov/24499732/)
<sup>[6]</sup> Qiu C, et al. (2014). Epigenetic mechanisms in neurodegenerative diseases. Nature Reviews Neurology 10(11):651-659. PMID: 25311587(https://pubmed.ncbi.nlm.nih.gov/25311587/)
<sup>[7]</sup> Coppedè F. (2014). The role of DNA methylation in neurodegenerative diseases. Aging and Disease 5(4):238-246. PMID: 25110612(https://pubmed.ncbi.nlm.nih.gov/25110612/)
<sup>[8]</sup>Gridley L, et al. (2013). Human DNA methyltransferases: A tale of dysregulation in cancer and neurodegeneration. Frontiers in Cell and Developmental Biology 1:12. PMID: 25364742(https://pubmed.ncbi.nlm.nih.gov/25364742/)