Gene: [DNMT3A](/genes/dnmt3a)
UniProt: [Q9Y6K1](https://www.uniprot.org/uniprot/Q9Y6K1)
Molecular Weight: ~130 kDa
Subcellular Localization: Nucleus
Protein Family: DNA methyltransferase family (DNMT3)
Overview
DNMT3A (DNA Methyltransferase 3A) is a de novo DNA methyltransferase that plays critical roles in epigenetic regulation. It is involved in neuronal development and has been implicated in age-related cognitive decline and neurodegenerative diseases.
Structure
DNMT3A is a large de novo DNA methyltransferase comprising multiple functional domains:
N-terminal regulatory domain: Contains the ADD (ATRX-DNMT3-DNMT3L) domain, which recognizes unmethylated histone H3 tails and mediates protein-protein interactions
PWWP domain: Binds to H3K36me3-modified nucleosomes, targeting DNMT3A to gene bodies
Bromo-adjacent homology (BAH) domain: Involved in chromatin recognition and regulatory functions
C-terminal catalytic domain: Contains the methyltransferase active site with conserved motifs (I, IV, VI, IX, X)
The protein forms tetramers and interacts with various chromatin modifiers and transcription factors.
Normal Function in the Nervous System
DNA methyltransferases are essential for establishing and maintaining [DNA methylation](/entities/dna-methylation) patterns, which regulate gene expression without changing the DNA sequence. In the nervous system, DNMT3A plays critical roles:
Epigenetic regulation of neurodevelopment: DNMT3A establishes new DNA methylation patterns during neuronal differentiation and brain development, particularly in prefrontal [cortex](/brain-regions/cortex) and hippocampal [neurons](/entities/neurons).
Synaptic plasticity: DNMT3A-mediated DNA methylation regulates genes involved in synaptic formation, function, and plasticity, including [NMDA receptor](/entities/nmda-receptor) subunits and AMPA receptor components.
Memory formation: Activity-dependent DNA methylation changes in the [hippocampus](/brain-regions/hippocampus) require DNMT3A for long-term memory consolidation.
Neuronal identity maintenance: DNMT3A helps maintain neuronal subtype identity by silencing alternative lineage programs through DNA methylation.
Glial cell development: DNMT3A is essential for astrocyte and oligodendrocyte differentiation from neural progenitors.
Role in Disease
Alzheimer's Disease (AD)
DNMT3A dysfunction contributes to AD pathogenesis through several mechanisms:
DNA methylation changes: Genome-wide hypomethylation and locus-specific hypermethylation are observed in AD brain. DNMT3A levels are reduced in AD neurons.
[Robertson KD, DNA methylation and human disease (2005)](https://pubmed.ncbi.nlm.nih.gov/16136652/))
[Feng J, Fan G, The role of DNA methylation in the central nervous system and neuropsychiatric disorders (2009)](https://pubmed.ncbi.nlm.nih.gov/19900617/))