Affinage

DNMT3A

DNA (cytosine-5)-methyltransferase 3A · UniProt Q9Y6K1

Length
912 aa
Mass
101.9 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNMT3A is a de novo DNA methyltransferase that establishes genome-wide CpG methylation patterns during embryogenesis and gametogenesis, acting upstream of and functionally cooperating with the maintenance enzyme DNMT1 (PMID:10555141, PMID:12383256). Catalysis proceeds through a target recognition domain in which Arg836/Asn838 contact the CpG guanine and couple base recognition to a 3'-pyrimidine flanking-sequence preference, while the RD loop (L883) tunes DNMT3A-specific DNA contacts; this intrinsic sequence preference shapes the cellular methylation landscape (PMID:32543182, PMID:36067881, PMID:29414941). Chromatin targeting is governed by the PWWP domain, which reads H3K36me2/me3 with higher affinity for the NSD1-deposited intergenic H3K36me2 mark, while the ADD domain senses the unmodified H3 tail to relieve an autoinhibitory closed conformation, and H3K36me3 further stimulates linker-DNA methylation independently of the PWWP domain by displacing the H3 tail (PMID:31485078, PMID:35236925). Engagement of nucleosomes is direct: DNMT3A contacts the H2A-H2B acidic patch and the H2AK119ub1 mark, with accessory subunits orienting catalysis on linker DNA (PMID:32968275, PMID:39043678). Activity is modulated by multiple partners—DNMT3L heterotetramers stimulate and redistribute the enzyme (PMID:23663978), PADI4 citrullination stabilizes it and boosts activity (PMID:24957603), MeCP2 binds the ADD domain to lock the autoinhibitory state (PMID:30102379), and CEBPA and arsenic respectively block substrate access and trigger degradation (PMID:35080973, PMID:35373418)—while transcription factors such as p63 and YAP/TAZ recruit it to specific loci (PMID:27476967, PMID:38380551). Beyond methylation, DNMT3A coordinates pre-mRNA splicing by recruiting SF3B1 and RNA polymerase in a catalysis-independent manner required for stem-cell state exit (PMID:37024683). Germline DNMT3A mutations cause Tatton-Brown-Rahman overgrowth syndrome by disrupting domain-domain interactions and histone binding (PMID:24614070), and the AML/clonal-hematopoiesis hotspot R882H/C mutations impair flanking-sequence readout and drive aberrant polymerization that exerts a dominant-negative reduction of methylation (PMID:29518238, PMID:32385248, PMID:38600075).

Mechanistic history

Synthesis pass · year-by-year structured walk · 31 steps
  1. 1999 High

    Established that DNMT3A is the enzyme responsible for setting up de novo methylation rather than maintaining it, defining its developmental role.

    Evidence Gene targeting/knockout in mouse ES cells and embryos with bisulfite sequencing

    PMID:10555141

    Open questions at the time
    • Did not resolve how DNMT3A is targeted to specific loci
    • Mechanism of cooperation with maintenance machinery undefined
  2. 2002 High

    Showed DNMT3A and DNMT1 cooperate through sequential activity, with de novo methylation priming maintenance methylation without physical contact.

    Evidence In vitro methylation assays with purified enzymes, sequential vs simultaneous incubation

    PMID:12383256

    Open questions at the time
    • Cellular relevance of in vitro stimulation not established
    • No structural basis provided
  3. 2013 Medium

    Defined DNMT3A/DNMT3L heterotetramers as a regulatory module that stimulates activity and redistributes the enzyme from heterochromatic filaments toward euchromatin.

    Evidence Biochemical reconstitution, structural and cellular localization analysis (review/synthesis)

    PMID:23663978

    Open questions at the time
    • Synthesis paper rather than single primary discovery
    • Physiological role of filament formation in vivo unclear
  4. 2013 Medium

    Placed DNMT3A in T-cell lineage control by showing it represses Th1 genes antagonistically to STAT4-driven chromatin remodeling.

    Evidence DNMT3A ChIP at target loci, conditional knockout, double-KO epistasis with IFN-γ assays

    PMID:23772023

    Open questions at the time
    • Recruitment mechanism to Th1 loci not defined
    • Single lab, no structural data
  5. 2014 Medium

    Linked DNMT3A to human overgrowth disease (Tatton-Brown-Rahman syndrome) and implicated PWWP/ADD/catalytic domain interactions in pathogenesis.

    Evidence Exome sequencing of patient cohort with protein structural modeling

    PMID:24614070

    Open questions at the time
    • No direct biochemical reconstitution of mutant activity
    • Functional consequence inferred from modeling
  6. 2014 High

    Identified PADI4 citrullination as a post-translational mechanism stabilizing DNMT3A and enhancing its methyltransferase activity.

    Evidence Co-IP, in vitro citrullination assay, pulse-chase stability, bisulfite pyrosequencing

    PMID:24957603

    Open questions at the time
    • Citrullinated residues' structural effect not resolved
    • Genome-wide impact untested
  7. 2016 High

    Demonstrated locus-specific recruitment via transcription factor partnership, with p63 directing DNMT3A to active enhancers to maintain epidermal stem cell function.

    Evidence ChIP-seq, genome-wide methylation profiling, siRNA depletion with stem cell assays

    PMID:27476967

    Open questions at the time
    • Mechanism coupling DNMT3A binding to hydroxymethylation maintenance incomplete
    • Direct p63-DNMT3A contact not structurally mapped
  8. 2018 High

    Provided the catalytic mechanism: a structure of DNMT3A-DNMT3L-DNA revealing dual CpG attack and the Arg836-mediated basis of CpG specificity, with cancer mutations causing hypomethylation.

    Evidence X-ray crystallography at 2.65 Å, in vitro methylation, mutagenesis, transformation assay

    PMID:29414941

    Open questions at the time
    • Nucleosomal substrate engagement not captured
    • Flanking-sequence dependence not fully resolved
  9. 2018 High

    Defined the R882H AML mutation mechanism as altered flanking-sequence preference rather than loss of DNA binding or stability.

    Evidence Biochemical methylation and kinetic assays with purified mutant protein, subnuclear localization

    PMID:29518238

    Open questions at the time
    • Did not explain dominant-negative behavior structurally
    • In vivo consequence of altered preference untested here
  10. 2018 High

    Established MeCP2 as a direct inhibitor that locks DNMT3A in its autoinhibited conformation via the ADD domain, relieved by unmodified H3 tail binding.

    Evidence In vitro binding/methylation assays, conformationally-locked DNMT3A variants, cellular methylation

    PMID:30102379

    Open questions at the time
    • Genomic loci affected by MeCP2 inhibition not mapped
    • Physiological contexts of regulation unclear
  11. 2019 High

    Identified NSD1-deposited H3K36me2 as the recruitment signal directing DNMT3A to intergenic regions, with the PWWP domain showing dual H3K36me2/me3 recognition.

    Evidence Genome-wide ChIP-seq, bisulfite sequencing, Nsd1/Nsd2 ablation, PWWP peptide binding assays

    PMID:31485078

    Open questions at the time
    • Quantitative contribution of me2 vs me3 in vivo not fully partitioned
    • Connection to disease mutations only inferred
  12. 2019 High

    Showed in vivo that PWWP-domain integrity restrains DNMT3A from Polycomb/bivalent chromatin, preventing aberrant hypermethylation and gene de-repression.

    Evidence Mouse D329A knock-in, whole-genome and non-CpG bisulfite sequencing

    PMID:31015495

    Open questions at the time
    • Generality across tissues beyond hypothalamus untested
    • Link to human TBRS phenotypes indirect
  13. 2019 Medium

    Extended DNMT3A function to mitochondrial DNA, where it shapes regional, strand-biased methylation correlating with transcript abundance.

    Evidence Strand-specific bisulfite sequencing, MeDIP, FspEI digestion, HPLC-MS, KO and overexpression

    PMID:31537639

    Open questions at the time
    • Mechanism of mitochondrial import/targeting unknown
    • Functional consequence of mtDNA methylation not causally tested
  14. 2020 High

    Resolved nucleosome engagement: cryo-EM of a DNMT3A2-DNMT3B3-nucleosome complex showed accessory-domain anchoring to the acidic patch orients catalysis on linker DNA.

    Evidence Cryo-EM structure determination

    PMID:32968275

    Open questions at the time
    • Conformational change repositioning nucleosomal DNA not directly observed
    • Catalytically engaged state not captured
  15. 2020 High

    Resolved how R882H structurally compromises catalysis—weakening the dimer-interface-to-TRD-loop coupling and increasing loop dynamics.

    Evidence X-ray crystallography of WT and mutant with DNA, in vitro methylation

    PMID:32385248

    Open questions at the time
    • Dominant-negative polymerization not yet explained
    • Cellular consequence not measured here
  16. 2020 High

    Defined the intrinsic catalytic sequence preference (3'-pyrimidine, TNC[G/A]CC) that directly patterns the genomic methylome.

    Evidence In vitro methylation of randomized DNA with deep bisulfite sequencing, triple-KO reintroduction

    PMID:32543182

    Open questions at the time
    • Interplay of intrinsic preference with chromatin targeting in vivo not separated
    • Non-CpG preference physiological role untested
  17. 2020 High

    Connected DNMT3A to inflammation resolution: it methylates Dusp4 using apoptotic-cell-derived methionine during efferocytosis to sustain pro-resolving signaling.

    Evidence Conditional bone-marrow KO mice, bisulfite sequencing, metabolic tracing, efferocytosis assays

    PMID:35361955

    Open questions at the time
    • Targeting mechanism to Dusp4 promoter not defined
    • Generalizability beyond macrophages untested
  18. 2020 Medium

    Revealed an epigenetic-memory role: DNMT3A methylates MAP1LC3 loci to durably repress autophagy genes after autophagy induction.

    Evidence DNA methylation assays, ChIP, siRNA knockdown, mouse/zebrafish models

    PMID:32876528

    Open questions at the time
    • Recruitment trigger to MAP1LC3 loci unclear
    • Single lab, locus-specific evidence
  19. 2021 High

    Showed DNMT3A loss in CAR T cells prevents exhaustion by blocking methylation-driven silencing of multipotency genes, defining a therapeutic methylation atlas.

    Evidence CRISPR KO in CAR T cells, genome-wide bisulfite sequencing, in vivo tumor challenge

    PMID:34788079

    Open questions at the time
    • Direct mechanism of exhaustion-gene targeting incomplete
    • Long-term safety of DNMT3A loss not addressed
  20. 2021 Medium

    Linked clonal-hematopoiesis DNMT3A loss to cardiac fibrosis via amplified HB-EGF release activating fibroblasts.

    Evidence Macrophage KO, fibroblast co-culture, conditioned medium, transcriptomics

    PMID:38242884

    Open questions at the time
    • Methylation target controlling HB-EGF not pinpointed
    • Single lab mechanistic chain
  21. 2022 High

    Uncovered a methylation-independent function: DNMT3A recruits SF3B1 and RNA polymerase to coordinate splicing required for stem-cell state exit.

    Evidence Reciprocal co-IP, catalytic-dead mutant rescue, RNA-seq splicing analysis

    PMID:37024683

    Open questions at the time
    • Structural basis of SF3B1 interaction unknown
    • Which transcripts depend on this function in vivo unclear
  22. 2022 High

    Mapped nucleosome recognition via H2AK119ub1: DNMT3A1 UDR contacts the acidic patch and ubiquitin mark, competing with the PRC2 cofactor JARID2.

    Evidence Cryo-EM structure, biochemical competition assays

    PMID:39043678

    Open questions at the time
    • Functional outcome of PRC2 competition in vivo untested
    • Isoform-specific UDR role not fully resolved
  23. 2022 High

    Systematic mutational scanning identified an interdomain interface controlling allosteric activation and a noncanonical PWWP-DNA-affinity function distinct from histone reading.

    Evidence Base editor scanning with methylation reporter, in vitro histone binding, stability assays

    PMID:36266353

    Open questions at the time
    • Structural detail of interdomain allostery not solved
    • Disease relevance of identified variants partly untested
  24. 2022 High

    Dissected CpG-guanine recognition and flanking readout at residue level (R836 conformational switching, N838, L883).

    Evidence In vitro methylation with randomized contexts, structure-guided mutagenesis, kinetics

    PMID:36067881

    Open questions at the time
    • Coupling to chromatin context not addressed
    • Effect of disease mutations on these residues only inferred
  25. 2022 High

    Identified isoform-specific inhibition: CEBPA blocks long-isoform DNMT3A substrate access, and AML CEBPA mutations relieve this to cause PRC2-target hypermethylation.

    Evidence Co-IP, in vitro inhibition assay, isoform mapping, bisulfite sequencing

    PMID:35080973

    Open questions at the time
    • Structural basis of isoform-selective binding unresolved
    • In vivo contribution to leukemogenesis not quantified
  26. 2022 High

    Showed H3K36me3 directly stimulates linker-DNA methylation independent of the PWWP domain, while absence of H3K4me3 relieves ADD autoinhibition.

    Evidence In vitro methylation of defined modified mononucleosomes with domain mutants

    PMID:35236925

    Open questions at the time
    • In vivo separation of these contributions untested
    • Mechanism by which H3K36me3 displaces H3 tail inferred
  27. 2022 Medium

    Established YAP/TAZ-directed recruitment of DNMT3A to the CDH1 promoter, driving E-cadherin silencing and cancer metastasis in a catalysis-dependent manner.

    Evidence Co-IP, ChIP, methylation-specific PCR/bisulfite, methyltransferase-dead rescue

    PMID:38380551

    Open questions at the time
    • Direct vs indirect YAP/TAZ-DNMT3A contact unclear
    • Single lab, single cancer context
  28. 2022 Medium

    Identified arsenic binding to the ADD domain as a trigger for proteasomal DNMT3A degradation and genome-wide hypomethylation.

    Evidence Direct binding assay, proteasome inhibitor rescue, ubiquitination assay, bisulfite sequencing

    PMID:35373418

    Open questions at the time
    • E3 ligase mediating degradation not identified
    • Single cell-type validation
  29. 2023 High

    Demonstrated in vivo that loss of substrate H3K36me2 (H3.3G34R) prevents DNMT3A recruitment, causing CG/CH methylation defects and neurodegeneration.

    Evidence H3.3G34R/V/W knock-in mice, chromatin profiling, DNMT3A ChIP, CG/CH bisulfite sequencing

    PMID:36931244

    Open questions at the time
    • Causality between methylation loss and neuroinflammation not fully dissected
    • Therapeutic reversibility untested
  30. 2024 High

    Explained the dominant-negative mechanism of R882H/C as enhanced intermolecular polymerization that occludes substrate, reversible by DNMT3B-converting mutations.

    Evidence X-ray crystallography, oligomerization assays, cellular/genomic methylation with engineered mutants

    PMID:38600075

    Open questions at the time
    • In vivo polymerization dynamics not visualized
    • Therapeutic targeting of polymerization untested
  31. 2025 High

    Revealed a metabolic vulnerability of R882H-equivalent mutant HSPCs—elevated mitochondrial respiration and membrane potential—targetable pharmacologically.

    Evidence Murine Dnmt3aR878H/+ model, OXPHOS assays, membrane potential, in vivo MitoQ/metformin treatment, prime-edited human HSPCs

    PMID:40240595 PMID:40240771

    Open questions at the time
    • Causal link between methylation defect and metabolic shift incompletely defined
    • Clinical translation of pharmacological targeting untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DNMT3A's intrinsic sequence preference, chromatin reader domains, transcription-factor recruitment, post-translational modifications, and methylation-independent splicing role are integrated into a single locus-selection logic in vivo remains unresolved.
  • No unified model linking targeting inputs to genome-wide outcome
  • Structural basis of methylation-independent SF3B1/RNA Pol interaction unknown
  • Mechanism partitioning nuclear vs mitochondrial DNMT3A undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0003677 DNA binding 3 GO:0016740 transferase activity 3 GO:0042393 histone binding 3 GO:0003723 RNA binding 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3 R-HSA-8953854 Metabolism of RNA 2
Partners
CEBPADNMT1DNMT3LMECP2PADI4SF3B1TP63YAP1
Complex memberships
DNMT3A-DNMT3L heterotetramerDNMT3A2-DNMT3B3-nucleosome complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Dnmt3a functions as a de novo DNA methyltransferase essential for establishing genome-wide methylation patterns during early embryogenesis and gametogenesis; genetic knockout in mice blocks de novo methylation in ES cells and early embryos but does not affect maintenance of imprinted methylation patterns. Gene targeting/knockout in mouse ES cells and embryos, bisulfite sequencing Cell High 10555141
2002 Dnmt3a and Dnmt1 functionally cooperate in de novo methylation: Dnmt3a-mediated initial methylation stimulates Dnmt1 activity on the same DNA substrate approximately 5-fold, without requiring physical interaction between the two enzymes (sequential activity suffices). In vitro methylation assay with purified enzymes, sequential incubation experiments European journal of biochemistry High 12383256
2013 DNMT3A forms a linear heterotetramer with DNMT3L that stimulates its catalytic activity; isolated DNMT3A forms protein filaments that bind multiple DNA molecules in parallel (supporting heterochromatic localization), and DNMT3L disrupts these filaments, redistributing the enzyme toward euchromatin. DNMT3A/3L heterotetramers cooperatively multimerize on DNA, leading to periodic methylation preference. Biochemical reconstitution, structural analysis, cellular localization studies Progress in molecular biology and translational science Medium 23663978
2014 DNMT3A mutations causing Tatton-Brown-Rahman overgrowth syndrome alter residues in the PWWP, ADD, and catalytic domains; protein modeling indicates these mutations interfere with domain-domain interactions and histone binding. Exome sequencing of patient cohort, protein structural modeling Nature genetics Medium 24614070
2014 PADI4 citrullination of DNMT3A at a sequence upstream of the PWWP domain stabilizes DNMT3A protein (prevents degradation) and increases its DNA methyltransferase activity; PADI4 physically interacts with DNMT3A both in vitro and in cells. Co-IP from overexpressed and endogenous cells, in vitro citrullination assay, pulse-chase protein stability assay, RNAi knockdown, bisulfite pyrosequencing of p21 promoter Nucleic acids research High 24957603
2016 In human epidermal stem cells, Dnmt3a binds active enhancers in an H3K36me3-dependent manner; Dnmt3a associates with p63 to maintain high levels of DNA hydroxymethylation at the center of enhancers in a Tet2-dependent manner, and depletion of Dnmt3a inactivates target enhancers and impairs epidermal stem cell function. ChIP-seq, genome-wide methylation profiling, siRNA depletion with functional stem cell assays Cell stem cell High 27476967
2018 Crystal structure of DNMT3A-DNMT3L-DNA complex at 2.65 Å shows two DNMT3A monomers simultaneously attacking two CpG dinucleotides separated by 14 bp; Arg836 of the target recognition domain (TRD) makes crucial contacts with CpG to ensure CpG specificity; haematological cancer-associated somatic mutations of substrate-binding residues decrease DNMT3A activity and induce CpG hypomethylation. X-ray crystallography (2.65 Å), in vitro methylation assays, mutagenesis, cellular transformation assay Nature High 29414941
2018 The R882H DNMT3A mutation reduces overall DNA methylation activity ~40% but does not change DNA binding affinity, protein stability, or subnuclear distribution; instead, R882 mediates indirect readout of flanking sequence preferences, and R882H causes pronounced changes in flanking sequence preference with site-specific activity changes (up to 7-fold reduction at disfavored sequences). Biochemical methylation assays with purified protein, kinetic analyses with designed substrates, subnuclear localization Nucleic acids research High 29518238
2018 MeCP2 directly interacts with DNMT3A through MeCP2's transcriptional repression domain and DNMT3A's ADD domain, strongly inhibiting DNMT3A activity in vitro by stabilizing the closed autoinhibitory conformation of DNMT3A; binding of unmodified H3 N-terminal tail to the ADD domain relieves MeCP2-mediated inhibition. In vitro binding and methylation assays, conformationally-locked DNMT3A variants as biochemical tools, cell overexpression with global methylation measurement Nucleic acids research High 30102379
2019 NSD1-mediated H3K36me2 is required for recruitment of DNMT3A to intergenic regions; genetic ablation of Nsd1/Nsd2 redistributes DNMT3A to H3K36me3-modified gene bodies and reduces intergenic DNA methylation. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3, with higher binding affinity toward H3K36me2, abrogated by TBRS-derived missense mutations. Genome-wide DNMT3A ChIP-seq, bisulfite sequencing, genetic Nsd1/Nsd2 ablation, in vitro histone peptide binding assays with PWWP domain Nature High 31485078
2019 Mutation of the PWWP domain (D329A) in DNMT3A in vivo causes redistribution of DNMT3A activity from H3K36me3-marked gene bodies to H3K27me3-marked and bivalent chromatin domains, resulting in progressive DNA hypermethylation at developmental regulatory gene loci and their de-repression in adult hypothalamus. Mouse knock-in model, whole-genome bisulfite sequencing, non-CpG methylation profiling as marker of de novo activity Nature communications High 31015495
2019 DNMT3A knockout alone perturbs regional (not global) mitochondrial DNA methylation patterns, predominantly at L-strand non-CpG sites at gene-gene boundaries; overexpression of DNMT3A increases mtDNA methylation and strand bias; mtDNA methylation at gene bodies and boundaries negatively correlates with mitochondrial transcript abundance. Bisulfite sequencing with strand-specific mapping, MeDIP, FspEI digestion, HPLC-MS, DNMT3A knockout and overexpression Genome research Medium 31537639
2020 Cryo-EM structure of DNMT3A2-DNMT3B3-nucleosome complex shows the catalytic-like domain of accessory DNMT3B3 binds to the acidic patch of the nucleosome core, orienting DNMT3A2 binding to linker DNA; steric constraints suggest nucleosomal DNA must be repositioned for de novo methylation to occur. Cryo-electron microscopy structure determination Nature High 32968275
2020 Structural characterization of wild-type and R882H-mutated DNMT3A bound to DNA substrates shows: the TRD loop recognizes CpG in a +1 flanking site-dependent manner; R882H reduces DNA binding at the homodimeric interface and weakens the molecular link between homodimeric interface and TRD loop, enhancing TRD loop dynamics and compromising enzymatic activity, CpG specificity, and flanking sequence preference. X-ray crystallography, in vitro methylation assays with multiple DNA substrates Nature communications High 32385248
2020 DNMT3A methylates the Dusp4 promoter using S-adenosylmethionine derived from apoptotic cell-derived methionine during macrophage efferocytosis, repressing Dusp4 expression and enabling sustained ERK phosphorylation required for the prostaglandin E2-TGFβ1 pro-resolving pathway; bone-marrow DNMT3A deletion blocks this resolution cascade. Conditional bone-marrow DNMT3A knockout mice, bisulfite sequencing, metabolic tracing, in vitro efferocytosis assays Nature metabolism High 35361955
2020 DNMT3A methylates MAP1LC3 gene loci upon autophagy stimulation, causing long-term transcriptional repression of MAP1LC3 isoforms (key autophagy components), providing an epigenetic memory of prior autophagy induction. DNA methylation assays, ChIP, siRNA knockdown, in vivo mouse/zebrafish models Autophagy Medium 32876528
2020 DNMT3A preferentially methylates CpG and non-CpG sites with a 3'-pyrimidine flanking preference (sequence preference for TNC[G/A]CC context); this inherent enzymatic sequence preference directly shapes the genomic DNA methylation landscape as shown by reintroduction into triple-knockout cells. In vitro methylation of randomized DNA sequences followed by deep bisulfite sequencing; validation using triple-knockout cell reintroduction experiments Biochemistry High 32543182
2021 DNMT3A inactivation in macrophages amplifies heparin-binding EGF-like growth factor (HB-EGF) release, which paracrinally activates cardiac fibroblasts and increases cardiac fibrosis, identifying a mechanism linking DNMT3A CHIP mutations to heart failure progression. DNMT3A KO in macrophages, co-culture with fibroblasts, conditioned medium experiments, transcriptomic profiling Nature communications Medium 38242884
2021 DNMT3A deletion in CAR T cells prevents exhaustion by blocking epigenetic silencing of genes (including CD28, CCR7, TCF7, LEF1) that maintain T cell multipotency; genome-wide DNA methylation profiling defined the atlas of DNMT3A-targeted epigenetically silenced genes during exhaustion. CRISPR KO of DNMT3A in CAR T cells, genome-wide bisulfite sequencing, in vitro and in vivo tumor challenge assays Science translational medicine High 34788079
2022 DNMT3A coordinates mRNA splicing by recruiting the core spliceosome protein SF3B1 to RNA polymerase and mRNA in response to differentiation stimuli; this function is independent of DNMT3A's DNA methyltransferase catalytic activity and is required for stem cell exit from the stem state. Co-IP of DNMT3A with SF3B1 and RNA polymerase, loss-of-function experiments, RNA-seq splicing analysis, catalytic-dead mutant rescue experiments Nature cell biology High 37024683
2022 DNMT3A interacts with spliceosome component SF3B1 and RNA Polymerase to influence mRNA processing, with the DNA methylation function of DNMT3A not required for this splicing role; loss of DNMT3A impairs splicing efficiency during stem cell activation. Co-IP, splicing efficiency analysis by RNA-seq, catalytic mutant experiments Nature cell biology High 37024683
2022 Cryo-EM structure of DNMT3A1's UDR fragment complexed with H2AK119ub1-modified nucleosome shows DNMT3A1 contacts the H2A-H2B acidic patch, a surface groove formed by H2A and H3, nucleosomal DNA, and H2AK119ub1; DNMT3A1 UDR competes with JARID2 (a PRC2 cofactor) for nucleosome binding. Cryo-EM structure determination, biochemical competition assays Nature communications High 39043678
2022 Base editor scanning of DNMT3A in situ identified mutations throughout the protein that perturb function; mutations at an interdomain interface block allosteric activation; mutations in the PWWP domain modulate enzyme activity through altered PWWP domain DNA affinity (a noncanonical function) rather than altered histone recognition or protein stability. Base editor scanning with DNA methylation reporter, in vitro histone binding assays, protein stability measurements Nature chemical biology High 36266353
2022 DNMT3A R836 and N838 residues mediate CpG guanine recognition and flanking sequence readout: R836 changes conformation depending on flanking sequence, contacting either CpG guanine or the +1/+2 flank and coupling CpG recognition to flanking sequence preference; L883 reduces DNMT3A activity by mediating DNMT3A-specific DNA interactions of the RD loop. In vitro methylation assays with randomized sequence contexts, structure-guided mutagenesis, kinetic analyses The Journal of biological chemistry High 36067881
2022 CEBPA interacts specifically with the long splice isoform DNMT3A (but not DNMT3A2), blocking DNMT3A access to DNA substrate and inhibiting its methyltransferase activity; AML-associated CEBPA mutations (e.g., CEBPAN321D) disrupt this interaction and cause aberrant DNA hypermethylation of PRC2 target genes. Co-IP, in vitro methylation inhibition assay, bisulfite sequencing of target loci, isoform-specific interaction mapping Science advances High 35080973
2022 H3K36me3 directly stimulates linker DNA methylation by DNMT3A in a manner independent of the DNMT3A PWWP domain, likely by preventing H3-tail interaction with linker DNA; H3K4me3 absence promotes linker DNA methylation by enabling H3-tail binding to the ADD domain and relieving autoinhibition. In vitro methylation of recombinant mononucleosomes containing defined histone modifications, DNMT3A and domain mutant comparisons Communications biology High 35236925
2022 Arsenic atoms directly bind to the cysteine-rich ADD domain of DNMT3A, triggering ubiquitin- and proteasome-mediated DNMT3A degradation and genome-wide DNA hypomethylation in embryonic fibroblasts. Direct binding assay (arsenic to ADD domain), proteasome inhibitor rescue, ubiquitination assay, genome-wide bisulfite sequencing EMBO reports Medium 35373418
2023 H3.3G34R mutation severely decreases H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNMT3A and its redistribution on chromatin, leading to loss of non-CG methylation at neuronal genes and ectopic CG methylation, causing neuroinflammation and neurodegeneration. H3.3G34R/V/W knock-in mice, genome-wide chromatin profiling, DNMT3A ChIP, bisulfite sequencing for CG and CH methylation Cell High 36931244
2024 DNMT3A R882H/C hotspot mutations enhance intermolecular contacts leading to DNMT3A polymerization (oligomerization); this aberrant oligomerization has a dominant-negative effect by reducing substrate access; introducing DNMT3B-converting mutations inhibits R882H/R882C-triggered polymerization and eliminates the dominant-negative effect. X-ray crystallography, biochemical oligomerization assays, cellular and genomic DNA methylation analyses with engineered mutations Nature communications High 38600075
2025 Dnmt3aR878H/+ mutant HSPCs have increased mitochondrial respiration and elevated mitochondrial membrane potential (Δψm) compared to wild-type; this metabolic reprogramming underlies their competitive advantage and can be selectively targeted by long-chain alkyl-TPP molecules (MitoQ, d-TPP) that accumulate in mitochondria of high-Δψm cells, causing apoptosis and ablating the selective advantage. Murine Dnmt3aR878H/+ model, oxidative phosphorylation functional assays, mitochondrial membrane potential measurement, in vivo MitoQ treatment with competitive transplantation Nature communications High 40240771
2025 Dnmt3aR878H/+ HSPCs have increased mitochondrial respiration compared to wild-type; metformin reduces their competitive advantage by enhancing methylation potential and reversing aberrant CpG DNA methylation and H3K27me3 profiles in mutant HSPCs. Murine competitive transplantation, multi-omics (DNA methylation, histone modification, metabolomics), metformin treatment, prime-edited human DNMT3AR882H HSPCs Nature High 40240595
2013 STAT4 establishes H3K4 methylation and Jmjd3 recruitment at target loci, reducing H3K27me3 and displacing DNMT3A; DNMT3A has an obligate role in repressing Th1 gene expression, and loss of both STAT4 and DNMT3A in T cells recovers Th1 gene expression sufficient to increase IFN-γ production. ChIP for DNMT3A at target loci, conditional Dnmt3a knockout mice, IFN-γ production assays, double-KO epistasis Journal of immunology Medium 23772023
2022 YAP/TAZ interact with and recruit DNMT3A to the CDH1 promoter CpG island, generating promoter hypermethylation that silences CDH1 (E-cadherin) and promotes epithelial-to-mesenchymal transition and gallbladder cancer metastasis; this metastasis-promoting effect depends on DNMT3A's DNA methyltransferase activity. Co-IP of DNMT3A with YAP/TAZ, ChIP at CDH1 promoter, methylation-specific PCR/bisulfite sequencing, methyltransferase-dead mutant rescue experiments Advanced science Medium 38380551

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 4577 10555141
2010 DNMT3A mutations in acute myeloid leukemia. The New England journal of medicine 1605 21067377
2010 Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nature neuroscience 787 20228804
2019 The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. Nature 414 31485078
2015 DNMT3A in haematological malignancies. Nature reviews. Cancer 391 25693834
2017 DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 319 28655780
2021 Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. Cell stem cell 291 33743191
2021 Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Science translational medicine 285 34788079
2014 Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell stem cell 281 25130491
2014 Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nature genetics 278 24614070
2018 Structural basis for DNMT3A-mediated de novo DNA methylation. Nature 261 29414941
2017 Efficient targeted DNA methylation with chimeric dCas9-Dnmt3a-Dnmt3L methyltransferase. Nucleic acids research 230 27899645
2016 DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nature genetics 218 27428748
2020 Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure. Circulation research 209 33155517
2002 Dnmt3a and Dnmt1 functionally cooperate during de novo methylation of DNA. European journal of biochemistry 205 12383256
2017 DNA epigenome editing using CRISPR-Cas SunTag-directed DNMT3A. Genome biology 172 28923089
2016 Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis. Cell stem cell 172 27476967
2002 Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis. Mechanisms of development 169 12351185
2017 DNMT3A in Leukemia. Cold Spring Harbor perspectives in medicine 156 28003281
2022 Macrophages use apoptotic cell-derived methionine and DNMT3A during efferocytosis to promote tissue resolution. Nature metabolism 135 35361955
2021 Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. The Journal of experimental medicine 134 34698806
2017 Dnmt3a restrains mast cell inflammatory responses. Proceedings of the National Academy of Sciences of the United States of America 125 28167789
2018 Structural Basis of DNMT1 and DNMT3A-Mediated DNA Methylation. Genes 116 30544982
2019 Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia. Biomarker insights 98 31105426
2020 Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B. Nature 93 32968275
2022 DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis. Nature genetics 92 35410378
2006 Dynamic expression of DNMT3a and DNMT3b isoforms during male germ cell development in the mouse. Developmental biology 92 16725135
2019 A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice. Nature communications 83 31015495
2019 The strand-biased mitochondrial DNA methylome and its regulation by DNMT3A. Genome research 78 31537639
2020 Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness. Stem cell reports 77 32220332
2014 The de novo DNA methyltransferase DNMT3A in development and cancer. Epigenetics 77 24589714
2024 Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss. Cell 76 38838669
2023 Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes. Nature cardiovascular research 76 39196062
2011 Expression of DNMT1 and DNMT3a are regulated by GLI1 in human pancreatic cancer. PloS one 73 22110720
2016 Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases. Advances in experimental medicine and biology 68 27826835
2015 Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia 65 26710888
2020 Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation. Nature communications 64 32385248
2020 An Important Role for DNMT3A-Mediated DNA Methylation in Cardiomyocyte Metabolism and Contractility. Circulation 63 32885664
2018 Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation. Blood 62 30366920
2024 DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts. Nature communications 58 38242884
2023 Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration. Cell 57 36931244
2022 DNMT3A and DNMT3B in Breast Tumorigenesis and Potential Therapy. Frontiers in cell and developmental biology 57 35620052
2023 Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis. Nature communications 53 37045808
2017 DNMT1, DNMT3A and DNMT3B proteins are differently expressed in mouse oocytes and early embryos. Journal of molecular histology 53 29027601
2013 microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer. Epigenetics 53 23959088
2007 Age and gender affect DNMT3a and DNMT3b expression in human liver. Cell biology and toxicology 53 17929180
2016 Impact of DNMT1 and DNMT3a forebrain knockout on depressive- and anxiety like behavior in mice. Neurobiology of learning and memory 50 27545441
2016 DNMT3A and TET2 in the Pre-Leukemic Phase of Hematopoietic Disorders. Frontiers in oncology 49 27597933
2017 Dnmt3a regulates T-cell development and suppresses T-ALL transformation. Leukemia 48 28321121
2014 Citrullination of DNMT3A by PADI4 regulates its stability and controls DNA methylation. Nucleic acids research 48 24957603
2013 Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation. Journal of immunology (Baltimore, Md. : 1950) 47 23772023
2012 Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 47 23031157
2025 Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs. Nature 46 40240595
2022 Base editor scanning charts the DNMT3A activity landscape. Nature chemical biology 42 36266353
2021 Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome. Nature communications 42 34315901
2020 LncRNA Dnmt3aos regulates Dnmt3a expression leading to aberrant DNA methylation in macrophage polarization. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 41 32052888
2018 The DNMT3A R882H mutant displays altered flanking sequence preferences. Nucleic acids research 41 29518238
2017 Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis. BioMed research international 39 28286768
2022 CD44v6 chimeric antigen receptor T cell specificity towards AML with FLT3 or DNMT3A mutations. Clinical and translational medicine 36 36163632
2020 Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis. Blood 35 31932841
2016 DNMT3A mutation leads to leukemic extramedullary infiltration mediated by TWIST1. Journal of hematology & oncology 34 27724883
2020 The DNA methyltransferase DNMT3A contributes to autophagy long-term memory. Autophagy 32 32876528
2020 Alterations to DNMT3A in Hematologic Malignancies. Cancer research 32 33087320
2018 SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 29750576
2022 UBA1 and DNMT3A mutations in VEXAS syndrome. A case report and literature review. Modern rheumatology case reports 31 34480172
2022 Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases. Advances in experimental medicine and biology 31 36350506
2017 DNMT3a methylation in neuropathic pain. Journal of pain research 31 29075135
2022 Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity. Science advances 30 35080973
2018 Chromatin-dependent allosteric regulation of DNMT3A activity by MeCP2. Nucleic acids research 30 30102379
2018 Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 29146735
2015 DNA methyltransferase DNMT3A associates with viral proteins and impacts HSV-1 infection. Proteomics 28 25758154
2020 Genome-wide DNA Methylation Signatures Are Determined by DNMT3A/B Sequence Preferences. Biochemistry 27 32543182
2022 Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis. eLife 26 35635747
2021 DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma. Cells 25 34831178
2025 Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis. Nature communications 24 40240771
2020 Dnmt3a and Dnmt3b-Decommissioned Fetal Enhancers are Linked to Kidney Disease. Journal of the American Society of Nephrology : JASN 24 32127410
2023 DNMT3A-coordinated splicing governs the stem state switch towards differentiation in embryonic and haematopoietic stem cells. Nature cell biology 23 37024683
2022 DNMT3A facilitates colorectal cancer progression via regulating DAB2IP mediated MEK/ERK activation. Biochimica et biophysica acta. Molecular basis of disease 23 35063646
2023 DNMT3a-dermatopontin axis suppresses breast cancer malignancy via inactivating YAP. Cell death & disease 22 36774339
2022 DNA methyltransferase DNMT3A forms interaction networks with the CpG site and flanking sequence elements for efficient methylation. The Journal of biological chemistry 22 36067881
2024 DNMT3A Cooperates with YAP/TAZ to Drive Gallbladder Cancer Metastasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 21 38380551
2024 Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction. Nature communications 21 39043678
2022 Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21. Blood cancer discovery 21 35394496
2014 Mutation and expression analysis of the IDH1, IDH2, DNMT3A, and MYD88 genes in colorectal cancer. Gene 21 24887488
2022 Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome. Haematologica 20 34092059
2022 ULK3-dependent activation of GLI1 promotes DNMT3A expression upon autophagy induction. Autophagy 20 35226587
2023 RNautophagic regulation of DNMT3a-dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer. Clinical and translational medicine 19 37477089
2022 CircPTPRM accelerates malignancy of papillary thyroid cancer via miR-885-5p/DNMT3A axis. Journal of clinical laboratory analysis 19 36098040
2021 DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in mature human immune cells. The Journal of experimental medicine 19 33970190
2022 DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks. Clinical cancer research : an official journal of the American Association for Cancer Research 18 34716195
2021 DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A. Biomolecules 18 34067359
2018 Variants of DNMT3A cause transcript-specific DNA methylation patterns and affect hematopoiesis. Life science alliance 18 30582132
2024 Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations. Nature communications 17 38600075
2022 Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation. EMBO reports 17 35373418
2022 DNMT3A R882H mutation drives daunorubicin resistance in acute myeloid leukemia via regulating NRF2/NQO1 pathway. Cell communication and signaling : CCS 17 36303144
2025 Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen. Cell reports 16 40178977
2022 Methylation of recombinant mononucleosomes by DNMT3A demonstrates efficient linker DNA methylation and a role of H3K36me3. Communications biology 16 35236925
2022 Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy. Blood advances 16 35413095
2021 Identification of RNA-binding proteins that partner with Lin28a to regulate Dnmt3a expression. Scientific reports 16 33504840
2013 Multimerization of the dnmt3a DNA methyltransferase and its functional implications. Progress in molecular biology and translational science 15 23663978

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