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FLASH GENE
Symbol DNMT3A contributors: shn/mct - updated : 01-06-2016
HGNC name DNA (cytosine-5-)-methyltransferase 3 alpha
HGNC id 2978
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
23 - 4395 - 912 ovary,thymus, spleen, testis 2001 11350943
  • displayed a localization pattern suggestive of euchromatin association
  • predominant form in embryonic stem cells and embryonal carcinoma cells
  • expression correlated with high de novo methylation activity
  • 19 - 3604 - 723 ubiquitous 2001 11350943
  • DNMT3A2, lacking the N-terminal 219 amino acid residues
  • 4 - 1808 - 166 - 2001 11350943
    23 - 4314 - 912 - 2001 11350943
    4 - 1737 - 166 - 2001 11350943
    18 - 3638 - 760 - 2001 11350943
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon highly
    Respiratoryrespiratory tractlarynx  highly
    cell lineage abundantly expressed in undifferentiated embryonic stem cells
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, pregnancy
    Text
  • placenta, embryo, in differentiated embryoid bodies
  • highly expressed during early embryonic development and down-regulated in most differentiated somatic cells
  • expressed in postnatal neural stem cells
  • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • DNA-binding activity of the N-terminal domain contributes to the DNA-methyltransferase activity via anchoring of the whole molecule to DNA under physiological salt conditions
  • cytosine-5 methyltransferase motifs
  • central cysteine-rich region with homology to ATRX (XNP)
  • five C terminal conserved catalytic domains
  • a long N-terminal regulatory region with a PWWP domain
  • a chromatin/chromosome-targeting module
  • a Tudor-like motif, involved in the protein-protein interaction between DNMT3A and PRMT5
  • a C-terminal domain responsible for the catalytic activity
  • conjugated
    mono polymer homomer , dimer
    HOMOLOGY
    interspecies ortholog to Dnmt3a, Mus musculus
    ortholog to dnmt3, Danio rerio
    Homologene
    FAMILY
  • C5-methyltransferase family
  • CATEGORY enzyme , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome,nucleosome
    intracellular,nucleus,chromatin/chromosome,euchromosome
    intracellular,nucleus,chromatin/chromosome,heterochromosome
    text
  • almost all of the cellular contents of DNMT3A/3B, but not DNMT1, are strongly anchored to a subset of nucleosomes
  • basic FUNCTION
  • essential for de novo DNA methylation and development
  • required for methylation of most imprinted loci in germ cells
  • upregulation of DNMT3A and TSIX implicated in delayed reprogramming of XIST/reactivation of inactive X chromosome after cell fusion
  • both a reader and a writer of repressive epigenetic marks, thereby directly linking histone and DNA methylation in gene silencing
  • mediate transcriptional repression
  • required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons
  • required for neurogenesis and may be used for maintaining active chromatin states of genes critical for development
  • Dnmt3a activity in nucleus accumbens is necessary for cocaine-induced increases in dendritic spine density selectively for the thin type of spines
  • probably involved in the pathogenesis of acute promonocytic or monocytic leukemia in elderly individuals, whereas MLL abnormalities might be associated with acute monoblastic leukemia in relatively young individuals
  • may act like a tumor-suppressor gene in lung tumor progression and may be a critical determinant of lung cancer malignancy
  • is a critical participant in the epigenetic silencing of hematopoietic stem cell (HSC) regulatory genes, thereby enabling efficient differentiation
  • DNMT3A and DNMT3B, but not the maintenance enzyme DNMT1, are redox-dependent DNA dehydroxymethylase
  • is required for the establishment of normal methylation patterns
  • role of DNMT3A in maintaining DNA methylation patterns in cancer
  • is required for efficient maintenance methylation of active chromosome domains and DNMT3A-deficient tumors show moderate levels of gene deregulation in these domains
  • DNMT3A, DNMT3B, DNMT1 roles in Ca(2+) ion-dependent biological processes, including the genome-wide/local DNA demethylation during early embryogenesis, cell differentiation, neuronal activity-regulated gene expression, and carcinogenesis
  • STAT4 and DNMT3A play opposing roles in regulating Th1 gene expression, and one mechanism for STAT4-dependent gene programming is in establishing a derepressed genetic state susceptible to transactivation by additional fate-determining transcription factors
  • de novo DNA methylating enzyme DNMT3A in postmitotic neurons is necessary for normal memory formation and its function cannot be substituted by the maintenance DNA methylating enzyme DNMT1
  • DNMT3A and DNMT3B have overlapping and distinct functions in hematopoietic stem cells
  • role for DNMT3A in the paraventricular nucleus of the hypothalamus (PVH) to link environmental conditions to altered energy homeostasis
  • regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway
  • DNMT3A and DNMT3B are critical to regulate the onset of IGK light chain rearrangement during early B-cell development
  • DNA dehydroxymethylation by DNMT3A, DNMT3B provides a simpler pathway to reduce DNA hydroxymethylation and methylation
  • moderates likely cognitive decline in subjects with mild cognitive impairment
  • DNMT3A and DNMT3B are primarily responsible for de novo methylation of specific cytosine residues in CpG dinucleotides during mammalian development
  • is important for enabling the activation of GBX2 expression, necessary for normal development of the inner ear
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development , neurogenesis
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA MIRN29s interacts with the 3-prime UTRs of DNMT3A
    small molecule
    protein
  • histone deacetylase 1, HDAC1
  • DNMT1 and DNMT3B
  • H3-K9 histone methyltransferase
  • C-terminal domain of human DNMT3L
  • E2 sumo conjugating enzyme Ubc9 and the E3 sumo ligases PIAS1 and PIASxalpha
  • v-myc myelocytomatosis viral oncogene homolog (avian), MYC
  • SET domain bifurcated 1, SETDB1
  • ZNF238 transcriptional repressor
  • interacts directly with PRMT5 and establishes the histone modification
  • specific interaction partner of CBX4 (promotes SUMOylation of DNMT3A)
  • H3 histone tail
  • interacting with MPHOSPH8
  • TCL1A physically interacts with DNA methylthansferases DNMT3A and DNMT3B
  • dual role for TET2 in promoting and inhibiting HSC differentiation, the loss of which, along with DNMT3A, obstructs differentiation, leading to transformation
  • cell & other
    REGULATION
    inhibited by SALL3
    Other stimulated by DNA (cytosine-5-)-methyltransferase 3-like , DNMT3L
    regulated at transcriptional level in nucleus accumbens by cocaine and chronic stress procedures
    ASSOCIATED DISORDERS
    corresponding disease(s) DNMT3OGS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in acute myeloid leukemia
    tumoral somatic mutation      
    in acute myelomonocytic leukemia (AML-M4)with poor prognosis
    tumoral   deletion    
    promotes lung tumor progression
    constitutional       loss of function
    its loss in hematopoietic stem cell (HSC)leads to the inhibition of differentiation and the hypomethylation of genes with a causal role in cancer
    tumoral somatic mutation      
    frequently mutated in T-ALL and is associated with distinct clinicopathologic entities and a poor prognosis
    tumoral     --over  
    by intragenic hypomethylation is associated with adverse prognosis in acute myeloid leukemia
    constitutional       loss of function
    disruption of DNMT3A or DNMT3B individually as well as of both enzymes in tandem results in viable, pluripotent cell lines with distinct effects on the DNA methylation landscape
    Susceptibility to Crohn disease
    Variant & Polymorphism other
  • increasing the risk of Crohn disease
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Dnmt3a(-/-) mice fail to establish maternal methylation imprints
  • disruption of Dnmt3a in female mouse germ cells, with its preservation in somatic cells mutant leads to death in utero and the lack of methylation and allele-specific expression at maternally imprinted loci
  • Dnmt3a conditional mutant males show impairment of spermatogenesis and lack methylation at two of three paternally imprinted loci in spermatogonia
  • conditional mutant mice lacking Dnmt1 and Dnmt3 in forebrain excitatory neurons have abnormal long-term plasticity in the hippocampal CA1 region with deficits in learning and memory
  • Dnmt3a-deficient mice had more grade 2 and grade 3 lung tumors than WT mice
  • Pml-Rara requires Dnmt3a to initiate acute promyelocytic leukemia (APL) in mice