Affinage

DNMT3L

DNA (cytosine-5)-methyltransferase 3-like · UniProt Q9UJW3

Length
386 aa
Mass
43.6 kDa
Annotated
2026-06-09
82 papers in source corpus 31 papers cited in narrative 32 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

DNMT3L is a catalytically inactive DNMT3-family protein that functions as an essential regulatory co-factor for de novo DNA methylation, coupling histone-mark reading to allosteric activation of the active methyltransferases (PMID:17687327, PMID:17713477). Its N-terminal cysteine-rich ADD/PHD-like domain specifically recognizes histone H3 tails unmethylated at lysine 4 (H3K4me0), an interaction abolished by H3K4 methylation and required for chromatin engagement and full germ-cell methylation in vivo (PMID:17687327, PMID:25683717). Its C-terminal domain binds the catalytic domains of DNMT3A and DNMT3B and organizes DNMT3A into a 3L-3a-3a-3L heterotetramer with two active sites spaced about one DNA helical turn apart, which multimerizes on DNA into nucleoprotein filaments and produces correlated methylation of CpG sites ~8–10 bp apart (PMID:17713477, PMID:18945701). Mechanistically, DNMT3L acts as a substrate-exchange factor that lowers Km for DNA and SAM, accelerates DNA binding, promotes an open active-site conformation, and enhances DNMT3A processivity, stimulating catalytic activity up to ~15-20 fold (PMID:15671018, PMID:16829525, PMID:20630873). Beyond enzyme activation, DNMT3L stabilizes DNMT3A2 protein against degradation (PMID:30321403), nucleates a repressive TRIM28/SETDB1/HDAC1/DNMT3A complex to enforce retrotransposon and retroviral silencing (PMID:12202768, PMID:12177302, PMID:24991018), and can be directed to specific loci through interactions with PRC2 and transcription factors (PMID:24074865, PMID:24952347). Genetically, DNMT3L is required to establish maternal genomic imprints in oocytes and de novo methylation of retrotransposons in male germ cells, and its loss causes biallelic imprinted-gene expression and azoospermia (PMID:11719692, PMID:15318244). DNMT3L is itself regulated post-translationally by SIRT1-mediated deacetylation and destabilization and by acetylation at K238/K412 (PMID:28228259, PMID:41781491).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Establishing that DNMT3L is a non-catalytic regulator rather than an active enzyme answered whether all DNMT3 family members methylate DNA directly, and tied DNMT3L function to genomic imprinting.

    Evidence Dnmt3L knockout in mice with bisulfite sequencing and allele-specific expression analysis

    PMID:11719692

    Open questions at the time
    • Did not define the molecular partner through which DNMT3L acts
    • Mechanism of imprint selectivity unresolved
  2. 2002 High

    Identifying physical and genetic links to DNMT3A/DNMT3B placed DNMT3L upstream of de novo methyltransferase activity and pointed to a co-factor mechanism.

    Evidence Co-IP, immunofluorescence co-localization, and double-mutant genetic epistasis in mice; episomal gain-of-function methylation assay in human cells

    PMID:11934864 PMID:12481029

    Open questions at the time
    • Did not distinguish recruitment from catalytic activation
    • Did not explain DNMT3A-specificity of stimulation in cells
  3. 2002 Medium

    Discovery that DNMT3L recruits HDAC1 via its PHD-like motif and represses transcription revealed a methylation-independent repressive function.

    Evidence GST pull-down, Co-IP, HDAC activity assay, and TSA-reversible reporter repression

    PMID:12177302 PMID:12202768

    Open questions at the time
    • Single lab
    • Did not establish endogenous loci targeted by HDAC recruitment
  4. 2004 High

    Defining the in vitro stimulatory mechanism showed DNMT3L acts directly on catalytic activity and cannot bind DNA on its own, ruling out a simple DNA-targeting model.

    Evidence In vitro methylation and binding assays with purified proteins plus truncation mapping; spermatogonial retrotransposon methylation analysis in knockout mice

    PMID:15105426 PMID:15318244

    Open questions at the time
    • Magnitude of stimulation modest in this assay
    • Locus selectivity for dispersed vs tandem repeats unexplained
  5. 2005 High

    Kinetic dissection established DNMT3L as a substrate-exchange factor that lowers Km for DNA and SAM and accelerates DNA binding, giving a quantitative mechanism for activation.

    Evidence In vitro methyltransferase kinetics, DNA- and AdoMet-binding assays, size-exclusion and pull-down; C-terminal interaction domain mapping

    PMID:15671018 PMID:15861382

    Open questions at the time
    • Used isolated catalytic/domain constructs in part
    • Did not yet have full-length structural picture
  6. 2006 High

    Full-length reconstitution and in vivo isoform analysis pinpointed DNMT3A2 as the relevant partner and showed DNMT3L reorganizes oligomers and boosts SAM binding.

    Evidence Full-length protein reconstitution with SEC, SAM/DNA-binding assays; Co-IP and localization rescue in ESCs and embryonic testes

    PMID:16829525 PMID:16999741

    Open questions at the time
    • DNMT3A2-specificity mechanism at structural level not defined
    • In vivo relevance of in vitro stimulation magnitudes unresolved
  7. 2006 Medium

    ICF-syndrome DNMT3B mutants linked the DNMT3L interaction surface to disease, showing the interaction is required for full DNMT3B function in vivo even when basal activity is intact.

    Evidence In vitro and episomal methylation assays plus Co-IP of ICF mutant DNMT3B with DNMT3L

    PMID:16543361

    Open questions at the time
    • Did not map the precise interface residues structurally
    • Single lab
  8. 2007 High

    Co-crystal structures resolved the two arms of DNMT3L function: H3K4me0 reading by the ADD domain and heterotetramer assembly with DNMT3A defining active-site spacing.

    Evidence Crystallography of DNMT3L with H3 peptide and of the DNMT3A-DNMT3L C-terminal complex, with interface mutagenesis and methylation periodicity assays

    PMID:17687327 PMID:17713477

    Open questions at the time
    • Used isolated domains rather than full-length nucleosomal complex
    • Did not capture transient substrate-exchange step
  9. 2008 High

    Demonstrating filament formation on DNA and identifying the RD interface as the DNA-binding site explained the periodic methylation pattern.

    Evidence Analytical ultracentrifugation, scanning force microscopy, hairpin bisulfite analysis, in vitro methylation

    PMID:18945701

    Open questions at the time
    • In vitro on naked DNA, not nucleosomes
    • Physiological filament length unknown
  10. 2010 Medium

    Processivity and flanking-sequence studies showed DNMT3L broadens and homogenizes methylation by enhancing processivity and attenuating intrinsic sequence preference on chromatin.

    Evidence In vitro processivity/single-hit kinetics and in vivo episomal bisulfite comparison on chromatinized vs naked DNA

    PMID:20630873 PMID:20838592

    Open questions at the time
    • Single lab assays
    • Endogenous chromatin context not directly tested
  11. 2011 Medium

    Defining DNMT3L as an oligomerization cap clarified how it controls DNMT3A multimerization and subnuclear localization, releasing DNMT3A from heterochromatin.

    Evidence In vitro oligomerization and DNA cross-linking assays plus cellular localization and overexpression

    PMID:21566127

    Open questions at the time
    • Functional consequence of heterochromatin release for methylation not fully mapped
    • Single lab
  12. 2014 Medium

    Identifying DNMT3L assembly of a TRIM28/SETDB1/HDAC1/DNMT3A repressive complex and broad TF interactions revealed methylation-independent silencing and locus-targeting mechanisms.

    Evidence Co-IP, ChIP for H3K9me3/acetylation, ectopic expression and retroviral integration assays; TF array with locus-specific bisulfite at TRAF1

    PMID:24952347 PMID:24991018

    Open questions at the time
    • Requirement of each complex member for silencing not fully dissected
    • TF-directed methylation shown at limited loci
  13. 2013 High

    Genome-wide analysis in ESCs revealed dual context-dependent regulation, with DNMT3L promoting gene-body methylation but protecting bivalent promoters via competition with PRC2.

    Evidence Genome-wide methylation profiling of knockdown ESCs, reciprocal PRC2 Co-IP, competition binding and differentiation assays

    PMID:24074865

    Open questions at the time
    • Mechanism of PRC2 competition at molecular level unresolved
    • Single lab
  14. 2015 High

    An ADD-domain point mutant separating H3K4me0 reading from other functions established histone-reading as essential for germline methylation and retrotransposon silencing.

    Evidence Knock-in point mutation in mice with whole-genome bisulfite sequencing and retrotransposon expression analysis

    PMID:25683717

    Open questions at the time
    • Relative contribution to CG vs non-CG methylation not fully separated
    • Single lab
  15. 2019 High

    Demonstrating DNMT3L stabilizes DNMT3A2 protein added a non-catalytic mechanism by which DNMT3L sustains methylation, distinct from direct activation.

    Evidence DNMT3L knockout ESCs with western blot, Co-IP, methylation analysis, and DNMT3A re-expression rescue

    PMID:30321403

    Open questions at the time
    • Degradation pathway protecting DNMT3A2 not identified
    • Partial rescue indicates additional functions remain
  16. 2017 Medium

    Identifying SIRT1-mediated deacetylation and destabilization established that DNMT3L levels are themselves controlled to set developmental methylation patterns.

    Evidence Co-IP, deacetylation and protein stability assays, methylation analysis, and Dnmt3L knockdown rescue in Sirt1-/- ESCs

    PMID:28228259

    Open questions at the time
    • Acetyltransferase acting on DNMT3L not identified here
    • Single lab
  17. 2021 Medium

    Discovery of methylation-independent functions through STAT and ECM-responsive nuclear import expanded DNMT3L into signaling-coupled differentiation control.

    Evidence Co-IP with STAT1/3, phospho-STAT blotting, conditional knock-in mice with inhibitor rescue; cell fractionation, ChIP at Nanog and stiffness manipulation

    PMID:33636226 PMID:34174172

    Open questions at the time
    • Direct vs indirect STAT activation mechanism unclear
    • Generality beyond neural/ESC contexts untested
  18. 2024 High

    Showing both DNMT3A-ADD and DNMT3L-ADD H3K4me0 readers are independently required, with synergy when both are lost, resolved the division of labor in chromatin reading.

    Evidence Single and double ADD loss-of-function knock-in mice with whole-genome bisulfite sequencing of germ cells

    PMID:38627502

    Open questions at the time
    • Spatial coordination of the two ADD domains on the nucleosome not defined
    • Non-CG methylation control mechanism incompletely understood
  19. 2026 Medium

    Mapping acetylation at K238/K412 as a stability switch placed DNMT3L under direct post-translational control linked to lineage potential.

    Evidence Mass spectrometry, site-directed mutagenesis, protein stability and methylation assays, differentiation assays

    PMID:41781491

    Open questions at the time
    • Enzymes writing/erasing K238/K412 not identified
    • Single lab, newly published

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DNMT3L coordinates histone reading, allosteric activation, complex assembly and its own post-translational regulation on an intact nucleosome in vivo remains incompletely resolved.
  • Full-length nucleosome-bound DNMT3A2-DNMT3L mechanism rests on a preprint cryo-EM model
  • Integration of stability, signaling and targeting functions at endogenous loci not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0042393 histone binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
DNMT3ADNMT3BEGR1HDAC1SETDB1SIRT1STAT3TRIM28
Complex memberships
DNMT3A-DNMT3L heterotetramer (3L-3a-3a-3L)DNMT3L-DNMT3B-NFkB-p65 ternary complexDNMT3L-PRC2 complexTRIM28/SETDB1/HDAC1/DNMT3A/DNMT3L repressive complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 DNMT3L specifically recognizes the extreme amino terminus of histone H3 tails that are unmethylated at lysine 4 (H3K4me0) via its N-terminal cysteine-rich (ADD/PHD-like) domain; this interaction is strongly inhibited by H3K4 methylation but insensitive to modifications at other positions, and it induces de novo DNA methylation by recruitment or activation of DNMT3A2. Crystallography of human DNMT3L co-crystallized with H3 tail peptide; peptide interaction assays; mass spectrometry identification of in vivo interactors; substitution of key binding-site residues Nature High 17687327
2007 The C-terminal domain of DNMT3L interacts with the catalytic domain of DNMT3A, forming a heterotetrameric complex (3L-3a-3a-3L) with two active sites separated by approximately one DNA helical turn; substitution of key residues at either the DNMT3A-DNMT3L (FF) or DNMT3A-DNMT3A (RD) interface eliminates enzymatic activity. DNMT3L thus has dual functions: binding unmethylated H3K4 and activating DNMT3A. Crystallography of human DNMT3A C-terminal domain complexed with DNMT3L C-terminal domain; mutagenesis of interface residues; DNA methylation periodicity assay Nature High 17713477
2001 Targeted disruption of Dnmt3L in mice prevents methylation of maternally imprinted sequences in oocytes, causing biallelic expression of paternally expressed imprinted genes in heterozygous progeny; males are azoospermic. DNMT3L lacks key catalytic motifs and acts as a regulator rather than an active methyltransferase. Gene knockout in mice; bisulfite genomic sequencing of oocyte and embryo DNA; allele-specific expression analysis Science High 11719692
2002 Dnmt3L interacts physically with DNMT3A and DNMT3B in co-immunoprecipitation and co-localizes with them in nuclei of transfected cells; Dnmt3L-deficient mice and [Dnmt3a-/-, Dnmt3b+/-] mice both fail to establish maternal methylation imprints, placing Dnmt3L upstream of Dnmt3 family enzymatic activity. Co-immunoprecipitation; immunofluorescence co-localization; genetic epistasis (double-mutant mice); bisulfite sequencing Development High 11934864
2004 Dnmt3L deletion in male mice prevents de novo methylation of both LTR and non-LTR retrotransposons specifically in non-dividing precursors of spermatogonial stem cells at the perinatal period, leading to retrotransposon transcription and meiotic failure. Pericentric tandem repeats are methylated normally, indicating selectivity for dispersed repeats. Gene knockout; bisulfite sequencing of retrotransposon sequences; immunohistochemistry for Dnmt3L expression; meiotic staging analysis Nature High 15318244
2002 Co-expression of DNMT3L with DNMT3A (but not DNMT3B) in human cells produces a striking stimulation of de novo methylation at imprinted and non-imprinted sequences on replicating episomes and at endogenous genomic sequences, establishing DNMT3L as a general stimulatory factor specifically for DNMT3A. Episome-based in vivo de novo methylation assay; bisulfite sequencing; co-transfection in human cells PNAS High 12481029
2004 Purified human DNMT3L directly binds DNMT3A and DNMT3B in vitro and enhances their DNA methylation activity ~1.5–3-fold in a dose-dependent manner. DNMT3L cannot bind DNA alone; the stimulatory effect is through the C-terminal half of DNMT3L acting directly on catalytic activity rather than by DNA targeting. In vitro DNA methylation assays with purified proteins; binding assays; truncation mapping Journal of Biological Chemistry High 15105426
2005 DNMT3L stimulates DNMT3A and DNMT3B catalytic activity ~15-fold by binding their catalytic domains via its own C-terminal domain. The interaction accelerates DNA binding by DNMT3A 20-fold, lowers Km for DNA and for SAM, and DNMT3L dissociates from DNMT3A after DNA binding, acting as a substrate exchange factor that promotes an open active-site conformation. In vitro methyltransferase kinetics with purified proteins; DNA-binding assays; AdoMet-binding assays; transient interaction demonstrated by size exclusion and pull-down Journal of Biological Chemistry High 15671018
2006 Full-length DNMT3A2 and DNMT3L reconstituted in physiological buffers show up to 20-fold stimulation of DNMT3A2 catalytic efficiency at equimolar ratio. DNMT3L alone does not significantly bind SAM but strongly increases SAM binding to DNMT3A2 without appreciably improving DNA binding. DNMT3L as monomer reorganizes heterogeneous DNMT3A2 oligomers into specific complexes. In vitro reconstitution with purified full-length proteins; size exclusion chromatography; SAM-binding assays; DNA-binding assays Journal of Biological Chemistry High 16829525
2008 DNMT3A C-terminal/DNMT3L C-terminal complexes form 2:2 heterotetramers confirmed by analytical ultracentrifugation; these multimerize on DNA into nucleoprotein filaments visualized by scanning force microscopy, shortening DNA ~1.5-fold. The RD (3a-3a) interface is the DNA binding site; both interfaces are required for AdoMet binding and catalytic activity. Correlated methylation of CG sites ~8–10 bp apart reflects the geometry of the two active sites. Analytical ultracentrifugation; scanning force microscopy; hairpin bisulfite analysis; DNA-binding assays; in vitro methylation Nucleic Acids Research High 18945701
2009 The ADD domain of DNMT3A (structurally similar to DNMT3L ADD) forms a crystal complex with the H3 tail, recognizing unmethylated H3K4; biochemical and NMR data show that DNMT3A ADD and HP1α chromodomain bind the H3 tail mutually exclusively, indicating de novo methylation requires alteration of chromatin structure. Crystal structure of DNMT3A ADD domain alone and in complex with H3 tail; NMR competition assay; biochemical binding assays EMBO Reports High 19834512
2002 DNMT3L interacts with HDAC1 both in vitro and in vivo, purifies HDAC activity from nuclear extracts, and represses transcription in a manner dependent on HDAC1 and relieved by TSA. Binding to HDAC1 and repressive function require the PHD-like motif of DNMT3L. In vitro GST pull-down; co-immunoprecipitation; HDAC activity assay; transcriptional repression reporter assay; TSA rescue Nucleic Acids Research Medium 12177302 12202768
2002 DNMT3L represses transcription through recruitment of HDAC activity; the PHD-like zinc finger of the ADD domain is the main repression motif. DNMT3L contains an active nuclear localization signal at amino acids 156–159. Reporter gene transcriptional repression assay; pull-down with HDAC1; nuclear localization signal deletion mapping Nucleic Acids Research Medium 12177302
2005 The C-terminus of DNMT3L is the sole region required for interaction with DNMT3A and DNMT3B; interaction occurs through their C-terminal catalytic domains. All four catalytically active human DNMT3A and DNMT3B isoforms are stimulated by DNMT3L in vivo. Episome-based in vivo methylation assay; domain-deletion Co-IP mapping; systematic isoform analysis Journal of Cellular Biochemistry Medium 15861382
2010 DNMT3A methylates 5–8 CpG sites processively on human promoters before 50% dissociation; DNMT3L enhances this processivity 3-fold, providing a mechanistic basis for DNMT3L-mediated activation of DNMT3A. In vitro processivity assay on defined DNA substrates; single-hit kinetics; comparison ± DNMT3L Journal of Biological Chemistry Medium 20630873
2011 DNMT3A forms homodimers via the FF interface and further oligomerizes via RD interfaces, allowing binding of parallel DNA molecules. DNMT3L (lacking RD interface) prevents Dnmt3a oligomerization beyond the heterotetramer and restricts binding to a single DNA molecule. Both Dnmt3a interfaces are necessary for heterochromatic localization; DNMT3L overexpression releases Dnmt3a from heterochromatin. In vitro oligomerization assays; DNA-binding cross-linking assays; cellular localization by immunofluorescence; overexpression experiments Journal of Biological Chemistry Medium 21566127
2013 In mouse ESCs, DNMT3L positively regulates DNA methylation at gene bodies of housekeeping genes but negatively regulates methylation at promoters of bivalent genes. DNMT3L interacts with the PRC2 Polycomb complex in competition with DNMT3A and DNMT3B, maintaining low methylation at H3K27me3 regions; DNMT3L is required for ESC differentiation into primordial germ cells. Genome-wide DNA methylation analysis of Dnmt3L knockdown ESCs; Co-immunoprecipitation with PRC2; competition binding assays; differentiation assays Cell High 24074865
2014 DNMT3L enhances the interaction among HDAC1, SETDB1, DNMT3A, and TRIM28/KAP1 in ES cells and orchestrates retroviral silencing. Ectopic DNMT3L in somatic cells recruits this TRIM28/HDAC1/SETDB1/DNMT3A/DNMT3L repressive complex to newly integrated retroviral DNA, causing H3K9me3 accumulation and reduced H3K9/H3K27 acetylation independently of de novo DNA methylation. The complex requires DNMT3L interaction with both DNMT3A and histone H3. Co-immunoprecipitation; ChIP for H3K9me3 and acetylation marks; ectopic expression in MEFs; retroviral integration assay; domain-function mapping Journal of Virology Medium 24991018
2019 DNMT3L forms a complex with DNMT3A2 and prevents DNMT3A2 protein degradation, thereby stabilizing DNMT3A2 levels in ESCs. DNMT3L deficiency causes downregulation of DNMT3A2 protein and consequent hypomethylation at DNMT3A target regions; restoring DNMT3A protein levels in DNMT3L-deficient cells partially recovers DNA methylation. DNMT3L knockout in mouse ESCs; western blotting for DNMT3A2; Co-IP; DNA methylation analysis; rescue by DNMT3A re-expression Nucleic Acids Research High 30321403
2010 DNMT3L modulates the flanking sequence preference of DNMT3A de novo methylation in two ways: it focuses the methylation machinery on chromatinized templates and attenuates the intrinsic sequence preference of DNMT3A by preferentially boosting methylation at poorly methylated sites, resulting in broader and more uniform methylation patterns. In vivo episomal methylation assay with extensive bisulfite sequencing; systematic comparison ± DNMT3L on chromatinized vs. naked DNA PLoS Genetics Medium 20838592
2006 In vivo, DNMT3L physically and functionally interacts selectively with DNMT3A2 (not DNMT3A or DNMT3B) in ESCs and embryonic testes. In ES cells lacking Dnmt3a, endogenous DNMT3L is mislocalized from chromatin foci to diffuse nuclear/cytoplasmic distribution; ectopic DNMT3A2 (but not DNMT3A or DNMT3B) restores Dnmt3L chromatin-foci localization. Co-immunoprecipitation from ES cells and embryonic testes; immunofluorescence localization; rescue by isoform-specific re-expression; bisulfite sequencing Genes to Cells Medium 16999741
2015 A single amino acid mutation in the DNMT3L ADD domain (H3K4me0-binding site) abolishes spermatogenesis in mice. Genome-wide single-base methylation analysis of mutant germ cells reveals reduced CG methylation at repetitive sequences and non-promoter CpG islands, and a more severe loss of non-CG methylation, coupled with retrotransposon reactivation. Gene targeting (knock-in point mutation); whole-genome bisulfite sequencing; retrotransposon expression analysis Cell Reports High 25683717
2006 Two ICF-syndrome DNMT3B mutant proteins (A766P and R840Q) retain near-wild-type basal methylation activity but show severely compromised interaction with DNMT3L and impaired stimulation by DNMT3L, both in vitro and in vivo, indicating that DNMT3L-DNMT3B interaction is required for full DNMT3B function in vivo. In vitro methylation assay; Co-IP of ICF mutant DNMT3B with DNMT3L; in vivo episomal methylation assay Human Molecular Genetics Medium 16543361
2017 SIRT1 physically interacts with DNMT3L protein, deacetylates it, and thereby destabilizes it. SIRT1 also suppresses Dnmt3L transcription. Loss of SIRT1 leads to elevated DNMT3L, which causes aberrant DNA methylation of developmental gene regulatory elements; Dnmt3L knockdown partially rescues the abnormal methylation in Sirt1-/- ESCs. Co-immunoprecipitation of SIRT1 with DNMT3L; deacetylation assay; protein stability assay; DNA methylation analysis; knockdown rescue Cell Reports Medium 28228259
2021 PKCα-dependent nuclear transport of DNMT3L is promoted by stiff extracellular matrix in mESCs; nuclear DNMT3L binds to Nanog promoter regions and is required for the enhanced DNA methylation of pluripotent gene promoters and loss of pluripotency gene expression under stiff ECM conditions. Cell fractionation; western blotting; ChIP of DNMT3L at Nanog promoter; PKCα inhibition/knockdown; bisulfite sequencing; hydrogel stiffness manipulation Advanced Healthcare Materials Medium 34174172
2014 DNMT3L interacts directly with 73 transcription factors in a TF array; 13 TFs interact exclusively with DNMT3L but not DNMT3A/B. DNMT3L forms a ternary complex with DNMT3B and NFκB-p65 that controls DNA methylation at the TRAF1 promoter in glioma cells, demonstrating that DNMT3L can direct sequence-specific methylation by tethering DNMT3A/B to sites via TF interactions. Transcription factor array (protein-protein interaction screen); Co-immunoprecipitation; bisulfite sequencing of TRAF1 promoter; knockdown experiments Biochimie Medium 24952347
2021 DNMT3L binds STAT1 and STAT3 proteins and increases their phosphorylation and nuclear translocation independently of DNA methylation, thereby activating transcription factors including HES3, ASCL1, NEUROD2, NEUROG2, and CDKN1A to promote neural differentiation. This function is rescued by STAT1/STAT3 phosphorylation inhibitors but not by a DNA methylation inhibitor. Co-immunoprecipitation of DNMT3L with STAT1/STAT3; phospho-STAT western blotting; conditional Dnmt3l knock-in mice; inhibitor rescue (Fludarabine, SH-4-54, Decitabine); gene expression analysis Progress in Neurobiology Medium 33636226
2024 Both the DNMT3A-ADD and DNMT3L-ADD domains, each recognizing H3K4me0, are independently required for full CG methylation in germ cells; loss of both ADD domains together causes a synergistic and more severe CG methylation reduction (comparable to Dnmt3a/3L double knockout) plus aberrant non-CG methylation accumulation at thousands of loci. Gene targeting of ADD domain loss-of-function substitutions in mice (single and double mutants); whole-genome bisulfite sequencing of oocytes and spermatozoa Nature Communications High 38627502
2025 Cryo-EM structures of nucleosome-bound full-length DNMT3A2-DNMT3L complex reveal that the DNMT3L C-terminal 'Switching Helix' adopts a conformation rotated 180° relative to DNMT3B3 on the nucleosome, preventing direct interaction with the acidic patch. The DNMT3L ADD domain promotes nucleosome binding while the DNMT3A PWWP domain inhibits it, indicating multi-layer regulation of chromatin engagement. Cryo-EM structure determination; in vitro nucleosome-binding assays; domain-function analysis bioRxivpreprint Medium
2020 Both H3K4me0 marks on both sister H3 tails of a nucleosome act cooperatively for Dnmt3a-Dnmt3L-mediated de novo DNA methylation; loss of H3K4me0 or H3K36me3 on one sister H3 dramatically reduces methylation, and mutations disrupting DNMT3L-ADD:H3K4me0 interaction cause significant reduction in DNA methylation. Bivalent histone H3 yeast system with ectopic Dnmt3a/Dnmt3L expression; systematic H3 tail mutations; 5mC quantification Journal of Genetics and Genomics Medium 32173286
2019 DNMT3L interacts with EGR1 to form a complex that binds the miR-195 promoter and represses its transcription in gastric cancer cells, representing a transcription factor-directed targeting mechanism for DNMT3L. Co-immunoprecipitation of EGR1 with DNMT3L; ChIP of EGR1 at miR-195 promoter; RT-PCR expression analysis; reporter assay Journal of Cellular and Molecular Medicine Low 31515938
2026 Acetylation of DNMT3L at lysine residues K238 and K412 controls its protein stability; site-specific acetylation modulates DNA methylation and lineage-specific developmental potential (germline, neural, cardiac) of mouse ES cells. Mass spectrometry identification of acetylation sites; site-directed mutagenesis of K238 and K412; protein stability assays; DNA methylation analysis; in vitro and in vivo differentiation assays Experimental & Molecular Medicine Medium 41781491

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 1152 17687327
2001 Dnmt3L and the establishment of maternal genomic imprints. Science (New York, N.Y.) 1020 11719692
2004 Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 895 15318244
2002 Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development (Cambridge, England) 738 11934864
2007 Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 624 17713477
2002 The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proceedings of the National Academy of Sciences of the United States of America 394 12481029
2004 DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. The Journal of biological chemistry 347 15105426
2009 Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO reports 305 19834512
2017 Efficient targeted DNA methylation with chimeric dCas9-Dnmt3a-Dnmt3L methyltransferase. Nucleic acids research 230 27899645
2005 Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L. The Journal of biological chemistry 228 15671018
2005 Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis. Proceedings of the National Academy of Sciences of the United States of America 220 15753313
2000 Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 217 10857753
2005 Physical and functional interactions between the human DNMT3L protein and members of the de novo methyltransferase family. Journal of cellular biochemistry 169 15861382
2006 Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L. The Journal of biological chemistry 143 16829525
2002 Dnmt3L is a transcriptional repressor that recruits histone deacetylase. Nucleic acids research 141 12202768
2013 Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs. Cell 137 24074865
2012 Targeted methylation and gene silencing of VEGF-A in human cells by using a designed Dnmt3a-Dnmt3L single-chain fusion protein with increased DNA methylation activity. Journal of molecular biology 130 23220192
2007 Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. Proceedings of the National Academy of Sciences of the United States of America 126 17609377
2019 DNMT3L facilitates DNA methylation partly by maintaining DNMT3A stability in mouse embryonic stem cells. Nucleic acids research 115 30321403
2010 DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo. PLoS genetics 104 20838592
2008 Formation of nucleoprotein filaments by mammalian DNA methyltransferase Dnmt3a in complex with regulator Dnmt3L. Nucleic acids research 99 18945701
2004 Co-expression of de novo DNA methyltransferases Dnmt3a2 and Dnmt3L in gonocytes of mouse embryos. Gene expression patterns : GEP 96 15567719
2011 Oligomerization and binding of the Dnmt3a DNA methyltransferase to parallel DNA molecules: heterochromatic localization and role of Dnmt3L. The Journal of biological chemistry 87 21566127
2006 Meiotic and epigenetic aberrations in Dnmt3L-deficient male germ cells. Molecular reproduction and development 83 16211598
2017 Sirt1 Regulates DNA Methylation and Differentiation Potential of Embryonic Stem Cells by Antagonizing Dnmt3l. Cell reports 82 28228259
2002 Imprinting regulator DNMT3L is a transcriptional repressor associated with histone deacetylase activity. Nucleic acids research 71 12177302
2007 Loss of spermatogonia and wide-spread DNA methylation defects in newborn male mice deficient in DNMT3L. BMC developmental biology 70 17875220
2010 The inherent processivity of the human de novo methyltransferase 3A (DNMT3A) is enhanced by DNMT3L. The Journal of biological chemistry 68 20630873
2006 Stochastic imprinting in the progeny of Dnmt3L-/- females. Human molecular genetics 56 16403808
2011 Modulation of Dnmt3b function in vitro by interactions with Dnmt3L, Dnmt3a and Dnmt3b splice variants. Nucleic acids research 54 21378119
2006 Dnmt3a2 targets endogenous Dnmt3L to ES cell chromatin and induces regional DNA methylation. Genes to cells : devoted to molecular & cellular mechanisms 54 16999741
2001 Isolation and initial characterization of the mouse Dnmt3l gene. Cytogenetics and cell genetics 54 11306809
2009 A systematic search for DNA methyltransferase polymorphisms reveals a rare DNMT3L variant associated with subtelomeric hypomethylation. Human molecular genetics 52 19246518
2008 Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development. Human molecular genetics 51 18544626
2006 Evolution of the vertebrate DNMT3 gene family: a possible link between existence of DNMT3L and genomic imprinting. Cytogenetic and genome research 51 16575165
2010 DNMT3L is a novel marker and is essential for the growth of human embryonal carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 46 20460473
2006 Sex-specific promoters regulate Dnmt3L expression in mouse germ cells. Human reproduction (Oxford, England) 46 17060371
2016 Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression. Human molecular genetics 45 26911678
2014 DNMT3L promotes quiescence in postnatal spermatogonial progenitor cells. Development (Cambridge, England) 45 24850856
2006 Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L. Human molecular genetics 43 16543361
2006 DNA methylation profile at the DNMT3L promoter: a potential biomarker for cervical cancer. Epigenetics 38 17965599
2019 EGR1 interacts with DNMT3L to inhibit the transcription of miR-195 and plays an anti-apoptotic role in the development of gastric cancer. Journal of cellular and molecular medicine 35 31515938
2015 The Dnmt3L ADD Domain Controls Cytosine Methylation Establishment during Spermatogenesis. Cell reports 35 25683717
2013 Plasticity in Dnmt3L-dependent and -independent modes of de novo methylation in the developing mouse embryo. Development (Cambridge, England) 31 23293288
2014 DNMT3L interacts with transcription factors to target DNMT3L/DNMT3B to specific DNA sequences: role of the DNMT3L/DNMT3B/p65-NFκB complex in the (de-)methylation of TRAF1. Biochimie 30 24952347
2009 CG dinucleotide periodicities recognized by the Dnmt3a-Dnmt3L complex are distinctive at retroelements and imprinted domains. Mammalian genome : official journal of the International Mammalian Genome Society 30 19921333
2021 Extracellular Matrix Stiffness Regulates DNA Methylation by PKCα-Dependent Nuclear Transport of DNMT3L. Advanced healthcare materials 27 34174172
2004 Epigenetic modifications affect Dnmt3L expression. The Biochemical journal 26 15015937
2006 Stimulation effect of Dnmt3L on the DNA methylation activity of Dnmt3a2. Journal of biochemistry 23 16945937
2014 Ectopic DNMT3L triggers assembly of a repressive complex for retroviral silencing in somatic cells. Journal of virology 22 24991018
2009 Reprogramming of HeLa cells upon DNMT3L overexpression mimics carcinogenesis. Epigenetics 21 19625766
2010 Hypomethylation of the DNMT3L promoter in ocular surface squamous neoplasia. Archives of pathology & laboratory medicine 20 20670142
2012 Genetic polymorphisms of DNMT3L involved in hypermethylation of chromosomal ends are associated with greater risk of developing ovarian endometriosis. The American journal of pathology 19 22401780
2011 DNMT3L is a regulator of X chromosome compaction and post-meiotic gene transcription. PloS one 17 21483837
2011 DNA methylation plays an important role in promoter choice and protein production at the mouse Dnmt3L locus. Developmental biology 16 21645502
2024 Combined and differential roles of ADD domains of DNMT3A and DNMT3L on DNA methylation landscapes in mouse germ cells. Nature communications 15 38627502
2021 DNMT3L promotes neural differentiation by enhancing STAT1 and STAT3 phosphorylation independent of DNA methylation. Progress in neurobiology 15 33636226
2020 Transient DNMT3L Expression Reinforces Chromatin Surveillance to Halt Senescence Progression in Mouse Embryonic Fibroblast. Frontiers in cell and developmental biology 13 32195249
2014 The CpG island encompassing the promoter and first exon of human DNMT3L gene is a PcG/TrX response element (PRE). PloS one 13 24743422
2011 Association between single-nucleotide polymorphisms of DNMT3L and infertility with azoospermia in Chinese men. Reproductive biomedicine online 13 22116073
2021 Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature. Epigenetics & chromatin 11 33750431
2025 Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome. Cell stem cell 10 39788122
2011 Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo. Chromosoma 10 21553025
2015 Dnmt3l-knockout donor cells improve somatic cell nuclear transfer reprogramming efficiency. Reproduction (Cambridge, England) 9 26159833
2012 Haploinsufficiency of the paternal-effect gene Dnmt3L results in transient DNA hypomethylation in progenitor cells of the male germline. Human reproduction (Oxford, England) 9 23159436
2019 Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline. Neurobiology of aging 8 30877840
2019 Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice. Molecular reproduction and development 7 30834655
2020 Both combinatorial K4me0-K36me3 marks on sister histone H3s of a nucleosome are required for Dnmt3a-Dnmt3L mediated de novo DNA methylation. Journal of genetics and genomics = Yi chuan xue bao 6 32173286
2024 DNMT3L inhibits hepatocellular carcinoma progression through DNA methylation of CDO1: insights from big data to basic research. Journal of translational medicine 5 38308276
2023 Efficient Targeted DNA Methylation with dCas9-Coupled DNMT3A-DNMT3L Methyltransferase. Methods in molecular biology (Clifton, N.J.) 5 36173573
2020 Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus. International journal of molecular sciences 5 32878077
2023 Expression analysis suggests that DNMT3L is required for oocyte de novo DNA methylation only in Muridae and Cricetidae rodents. Epigenetics & chromatin 4 37924163
2022 Effects of transgene insertion loci and copy number on Dnmt3L gene silencing through antisense transgene-derived PIWI-interacting RNAs. RNA (New York, N.Y.) 4 35145000
2021 Transcriptome Analysis of Dnmt3l Knock-Out Mice Derived Multipotent Mesenchymal Stem/Stromal Cells During Osteogenic Differentiation. Frontiers in cell and developmental biology 4 33718357
2016 DNMT3L enables accumulation and inheritance of epimutations in transgenic Drosophila. Scientific reports 3 26795243
2025 Metformin activates autophagy and inhibits apoptosis and fetal heart abnormalities via the Dnmt3l/Usp18/STAT1 pathway. European journal of pharmacology 1 40738360
2026 Uncovering the acetylation sites of Dnmt3L that regulate protein stability and differentiation potency in embryonic stem cells. Experimental & molecular medicine 0 41781491
2026 Epigenetic orchestration by DNMT3B and DNMT3L throughout oocyte maturation. Histochemistry and cell biology 0 42184030
2026 SUMO3/RUNX1/AIRE/RCAN1 and DNMT3L/DYRK1A/Let-7c-5p/VEGF axes: immune dysregulation and genetic susceptibility as pulmonary risk factors in Down syndrome. 3 Biotech 0 42245386
2025 An Nlrp5-null mutation leads to attenuated de novo methylation in oocytes, accompanied by a significant reduction in DNMT3L. Molecular human reproduction 0 41252458
2024 DNMT3L interacts with Piwi and modulates the expression of piRNAs in transgenic Drosophila. Epigenomics 0 38440884
2015 Association between DNMT3L polymorphic variants and the risk of endometriosis-associated infertility. Molecular medicine reports 0 26647998

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