DNMT3L

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000792 heterochromatin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Heterochromatin location transferred from mouse Dnmt3l (Ensembl Compara). Consistent with DNMT3L's role in de novo methylation of retrotransposons and imprinted regions, but not its specific site of action. Reason: DNMT3L directs de novo methylation at retrotransposons and imprinting control regions that become heterochromatic, so association with heterochromatin is plausible. However DNMT3L's reader activity targets H3K4-unmethylated chromatin generally, not a heterochromatin-specific mark, so this is retained as a non-core location. Supporting Evidence: PMID:15318244 Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes. PMID:17687327 These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.
GO:0000794 condensed nuclear chromosome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Condensed nuclear chromosome location transferred from mouse. Mouse Dnmt3l is expressed in perinatal non-dividing prospermatogonia, not in meiotic spermatocytes, so association with condensed meiotic chromosomes is not where it functions. Reason: The source mouse annotation is experimental and has not been examined here, so it is not removed. DNMT3L acts on interphase chromatin in prospermatogonia and oocytes; mouse Dnmt3l is absent from spermatocytes. Any condensed-chromosome association is peripheral to its function. Supporting Evidence: PMID:15318244 is expressed in testes during a brief perinatal period in the non-dividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation.
GO:0005515 protein binding	IPI PMID:12202768 Dnmt3L is a transcriptional repressor that recruits histone ...	MODIFY	Summary: IPI with HDAC1 (Deplus et al. 2002). The interaction is functional: DNMT3L binds HDAC1 through its PHD-like (ADD) motif and represses transcription in an HDAC-dependent manner. Reason: The generic protein binding term can be replaced by the more informative histone deacetylase binding, which is directly supported by the paper and which already appears for this gene as enzyme binding from the same study. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:12202768 Here, we show that Dnmt3L, like Dnmt3a and Dnmt3b, interacts both in vitro and in vivo with the histone deacetylase HDAC1. PMID:12202768 Binding of Dnmt3L to HDAC1 as well as its repressive function require the PHD-like motif.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	REMOVE	Summary: High-throughput yeast two-hybrid interaction with RSL24D1 (PMID:16189514). The binary interactome screens do not indicate a functional role for this interaction. Reason: Bare protein binding from a binary interactome screen is uninformative; no biological role of a DNMT3L-RSL24D1 interaction is known. Removal reflects lack of functional information, not that the interaction is false.
GO:0005515 protein binding	IPI PMID:17713477 Structure of Dnmt3a bound to Dnmt3L suggests a model for de ...	MODIFY	Summary: IPI with DNMT3A from the DNMT3A-DNMT3L crystal structure (Jia et al. 2007). The interaction is the means by which DNMT3L activates DNMT3A. Reason: The DNMT3A interaction is the structural basis of DNMT3L's enzyme activator activity; interface substitutions abolish DNMT3A activity. The informative molecular function is enzyme activator activity, already annotated to DNMT3L. Proposed replacements: enzyme activator activity Supporting Evidence: PMID:17713477 the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase. PMID:17713477 Substitution of key non-catalytic residues at the Dnmt3a-Dnmt3L interface or the Dnmt3a-Dnmt3a interface eliminated enzymatic activity.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: High-throughput yeast two-hybrid interaction with RSL24D1 (PMID:25416956). The binary interactome screens do not indicate a functional role for this interaction. Reason: Bare protein binding from a binary interactome screen is uninformative; no biological role of a DNMT3L-RSL24D1 interaction is known. Removal reflects lack of functional information, not that the interaction is false.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction with PDZD4 (PMID:32296183). The binary interactome screens do not indicate a functional role for this interaction. Reason: Bare protein binding from a binary interactome screen is uninformative; no biological role of a DNMT3L-PDZD4 interaction is known. Removal reflects lack of functional information, not that the interaction is false.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction with RSL24D1 (PMID:32296183). The binary interactome screens do not indicate a functional role for this interaction. Reason: Bare protein binding from a binary interactome screen is uninformative; no biological role of a DNMT3L-RSL24D1 interaction is known. Removal reflects lack of functional information, not that the interaction is false.
GO:0005634 nucleus	HDA PMID:16780588 Cell array-based intracellular localization screening reveal...	ACCEPT	Summary: Nuclear localization is well supported and is where DNMT3L acts. Reason: DNMT3L reads histone H3 tails on chromatin and assembles with DNMT3A/DNMT3B on genomic DNA, so the nucleus is where its activity is executed. Mouse Dnmt3l co-localizes with Dnmt3a/3b in nuclei of transfected cells, and the human protein binds nucleosomal histone H3 directly. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells PMID:17687327 Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions.
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Nuclear localization is well supported and is where DNMT3L acts. Reason: DNMT3L reads histone H3 tails on chromatin and assembles with DNMT3A/DNMT3B on genomic DNA, so the nucleus is where its activity is executed. Mouse Dnmt3l co-localizes with Dnmt3a/3b in nuclei of transfected cells, and the human protein binds nucleosomal histone H3 directly. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells PMID:17687327 Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Nuclear localization is well supported and is where DNMT3L acts. Reason: DNMT3L reads histone H3 tails on chromatin and assembles with DNMT3A/DNMT3B on genomic DNA, so the nucleus is where its activity is executed. Mouse Dnmt3l co-localizes with Dnmt3a/3b in nuclei of transfected cells, and the human protein binds nucleosomal histone H3 directly. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells PMID:17687327 Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions.
GO:0005634 nucleus	NAS PMID:12202768 Dnmt3L is a transcriptional repressor that recruits histone ...	ACCEPT	Summary: Nuclear localization is well supported and is where DNMT3L acts. Reason: DNMT3L reads histone H3 tails on chromatin and assembles with DNMT3A/DNMT3B on genomic DNA, so the nucleus is where its activity is executed. Mouse Dnmt3l co-localizes with Dnmt3a/3b in nuclei of transfected cells, and the human protein binds nucleosomal histone H3 directly. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells PMID:17687327 Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions.
GO:0005634 nucleus	NAS PMID:25383530 Structural insight into autoinhibition and histone H3-induce...	ACCEPT	Summary: Nuclear localization is well supported and is where DNMT3L acts. Reason: DNMT3L reads histone H3 tails on chromatin and assembles with DNMT3A/DNMT3B on genomic DNA, so the nucleus is where its activity is executed. Mouse Dnmt3l co-localizes with Dnmt3a/3b in nuclei of transfected cells, and the human protein binds nucleosomal histone H3 directly. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells PMID:17687327 Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions.
GO:0005634 nucleus	NAS PMID:32083663 Structural insights into CpG-specific DNA methylation by hum...	ACCEPT	Summary: Nuclear localization is well supported and is where DNMT3L acts. Reason: DNMT3L reads histone H3 tails on chromatin and assembles with DNMT3A/DNMT3B on genomic DNA, so the nucleus is where its activity is executed. Mouse Dnmt3l co-localizes with Dnmt3a/3b in nuclei of transfected cells, and the human protein binds nucleosomal histone H3 directly. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells PMID:17687327 Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions.
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Cytoplasmic/cytosolic location; not the site of DNMT3L activity. Reason: A cytoplasmic pool is plausible (DNMT3L is synthesized there and the HDA screen of chromosome 21 proteins reports both nucleus and cytosol), but none of DNMT3L's known activities, i.e. histone H3 reading and DNMT3A/3B activation, are executed in the cytoplasm. The IBA node (PTN002747444) is seeded by DNMT3A/3B annotations. Kept as a non-core location rather than removed. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells
GO:0005737 cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cytoplasmic/cytosolic location; not the site of DNMT3L activity. Reason: A cytoplasmic pool is plausible (DNMT3L is synthesized there and the HDA screen of chromosome 21 proteins reports both nucleus and cytosol), but none of DNMT3L's known activities, i.e. histone H3 reading and DNMT3A/3B activation, are executed in the cytoplasm. The IBA node (PTN002747444) is seeded by DNMT3A/3B annotations. Kept as a non-core location rather than removed. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells
GO:0005829 cytosol	HDA PMID:16780588 Cell array-based intracellular localization screening reveal...	KEEP AS NON CORE	Summary: Cytoplasmic/cytosolic location; not the site of DNMT3L activity. Reason: A cytoplasmic pool is plausible (DNMT3L is synthesized there and the HDA screen of chromosome 21 proteins reports both nucleus and cytosol), but none of DNMT3L's known activities, i.e. histone H3 reading and DNMT3A/3B activation, are executed in the cytoplasm. The IBA node (PTN002747444) is seeded by DNMT3A/3B annotations. Kept as a non-core location rather than removed. Supporting Evidence: PMID:11934864 We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells
GO:0006346 DNA methylation-dependent constitutive heterochromatin formation	IEA GO_REF:0000107	ACCEPT	Summary: DNMT3L is a non-catalytic but essential subunit of the de novo DNA methylation machinery: it binds the DNMT3A/3B catalytic domain, stimulates catalysis and couples it to H3K4-unmethylated chromatin. Mouse Dnmt3l knockouts fail to establish de novo methylation of imprints and retrotransposons. Reason: DNMT3L does part of the work of this process rather than merely being required for it: its C-terminal domain forms the DNMT3L-DNMT3A-DNMT3A-DNMT3L heterotetramer whose interfaces are needed for catalysis, and its ADD domain reads unmethylated H3K4. The human biochemistry plus the mouse genetics (ortholog in the same PANTHER subfamily SF13) support the transfer. Supporting Evidence: PMID:17713477 Substitution of key non-catalytic residues at the Dnmt3a-Dnmt3L interface or the Dnmt3a-Dnmt3a interface eliminated enzymatic activity. PMID:17687327 These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2. PMID:15318244 Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes.
GO:0006346 DNA methylation-dependent constitutive heterochromatin formation	ISS GO_REF:0000024	ACCEPT	Summary: DNMT3L is a non-catalytic but essential subunit of the de novo DNA methylation machinery: it binds the DNMT3A/3B catalytic domain, stimulates catalysis and couples it to H3K4-unmethylated chromatin. Mouse Dnmt3l knockouts fail to establish de novo methylation of imprints and retrotransposons. Reason: DNMT3L does part of the work of this process rather than merely being required for it: its C-terminal domain forms the DNMT3L-DNMT3A-DNMT3A-DNMT3L heterotetramer whose interfaces are needed for catalysis, and its ADD domain reads unmethylated H3K4. The human biochemistry plus the mouse genetics (ortholog in the same PANTHER subfamily SF13) support the transfer. Supporting Evidence: PMID:17713477 Substitution of key non-catalytic residues at the Dnmt3a-Dnmt3L interface or the Dnmt3a-Dnmt3a interface eliminated enzymatic activity. PMID:17687327 These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2. PMID:15318244 Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes.
GO:0007141 male meiosis I	IEA GO_REF:0000107	REMOVE	Summary: Male meiosis I transferred from mouse Dnmt3l. Meiotic failure in Dnmt3l-null spermatocytes is a downstream consequence of failed premeiotic de novo methylation; Dnmt3l is not expressed in spermatocytes. Reason: DNMT3L cannot participate in meiosis I in cells where it is not expressed. Bourc'his and Bestor (2004) show that the meiotic catastrophe arises in spermatocytes that do not express Dnmt3L, after earlier loss of retrotransposon methylation in prospermatogonia. This is an indirect organismal phenotype, not process participation, so the electronic and ISS transfers are removed. Supporting Evidence: PMID:15318244 Loss of Dnmt3L from early germ cells also caused meiotic failure in spermatocytes, which do not express Dnmt3L. PMID:15318244 is expressed in testes during a brief perinatal period in the non-dividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation.
GO:0007141 male meiosis I	ISS GO_REF:0000024	REMOVE	Summary: Male meiosis I transferred from mouse Dnmt3l. Meiotic failure in Dnmt3l-null spermatocytes is a downstream consequence of failed premeiotic de novo methylation; Dnmt3l is not expressed in spermatocytes. Reason: DNMT3L cannot participate in meiosis I in cells where it is not expressed. Bourc'his and Bestor (2004) show that the meiotic catastrophe arises in spermatocytes that do not express Dnmt3L, after earlier loss of retrotransposon methylation in prospermatogonia. This is an indirect organismal phenotype, not process participation, so the electronic and ISS transfers are removed. Supporting Evidence: PMID:15318244 Loss of Dnmt3L from early germ cells also caused meiotic failure in spermatocytes, which do not express Dnmt3L. PMID:15318244 is expressed in testes during a brief perinatal period in the non-dividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation.
GO:0007283 spermatogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Spermatogenesis (ISS from mouse). Dnmt3l-null males are azoospermic because germline de novo methylation fails. Reason: DNMT3L acts in perinatal prospermatogonia to establish methylation, and its loss blocks spermatogenesis. This is a genuine but broad developmental involvement, so it is kept as non-core; the mechanistic core is de novo methylation. Supporting Evidence: PMID:11934864 In addition, both Dnmt3a and Dnmt3L are required for spermatogenesis. PMID:15318244 is expressed in testes during a brief perinatal period in the non-dividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation. file:human/DNMT3L/DNMT3L-deep-research-falcon.md Dnmt3l-null male mice are infertile and develop germ-cell depletion, delayed meiotic entry, abnormal homologous-chromosome synapsis, and subsequent apoptosis.
GO:0008047 enzyme activator activity	IBA GO_REF:0000033	ACCEPT	Summary: DNMT3L stimulates the catalytic activity of DNMT3A and DNMT3B by binding their catalytic domains, without itself having methyltransferase activity. Reason: Directly shown for human DNMT3L: DNMT3B stimulation (Xie et al. 2006, the IDA source), and DNMT3A activation through the heterotetramer interface (Jia et al. 2007). The IBA node PTN001891074 is the DNMT3L clade itself (donors are mouse Dnmt3l and human DNMT3L), so the inference stays within subfamily SF13 and does not extend the activator role to the catalytic paralogs. Supporting Evidence: PMID:16543361 However, their stimulation by DNMT3L was severely compromised due to deficient protein interaction. PMID:16543361 methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. PMID:17713477 the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase.
GO:0008047 enzyme activator activity	IDA PMID:16543361 Mutations in DNA methyltransferase DNMT3B in ICF syndrome af...	ACCEPT	Summary: DNMT3L stimulates the catalytic activity of DNMT3A and DNMT3B by binding their catalytic domains, without itself having methyltransferase activity. Reason: Directly shown for human DNMT3L: DNMT3B stimulation (Xie et al. 2006, the IDA source), and DNMT3A activation through the heterotetramer interface (Jia et al. 2007). The IBA node PTN001891074 is the DNMT3L clade itself (donors are mouse Dnmt3l and human DNMT3L), so the inference stays within subfamily SF13 and does not extend the activator role to the catalytic paralogs. Supporting Evidence: PMID:16543361 However, their stimulation by DNMT3L was severely compromised due to deficient protein interaction. PMID:16543361 methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. PMID:17713477 the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase.
GO:0008047 enzyme activator activity	IEA GO_REF:0000107	ACCEPT	Summary: DNMT3L stimulates the catalytic activity of DNMT3A and DNMT3B by binding their catalytic domains, without itself having methyltransferase activity. Reason: Directly shown for human DNMT3L: DNMT3B stimulation (Xie et al. 2006, the IDA source), and DNMT3A activation through the heterotetramer interface (Jia et al. 2007). The IBA node PTN001891074 is the DNMT3L clade itself (donors are mouse Dnmt3l and human DNMT3L), so the inference stays within subfamily SF13 and does not extend the activator role to the catalytic paralogs. Supporting Evidence: PMID:16543361 However, their stimulation by DNMT3L was severely compromised due to deficient protein interaction. PMID:16543361 methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. PMID:17713477 the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase.
GO:0019899 enzyme binding	IPI PMID:12202768 Dnmt3L is a transcriptional repressor that recruits histone ...	MODIFY	Summary: IPI with HDAC1 (Deplus et al. 2002). Correct, but histone deacetylase binding is the more specific supported term. Reason: Enzyme binding is true but general; the partner is HDAC1, so the is_a descendant histone deacetylase binding is the precise term. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:12202768 Here, we show that Dnmt3L, like Dnmt3a and Dnmt3b, interacts both in vitro and in vivo with the histone deacetylase HDAC1.
GO:0035098 ESC/E(Z) complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Colocalizes_with ESC/E(Z) (PRC2) complex, transferred from mouse. In mouse ESCs Dnmt3l interacts with PRC2 (EZH2) in competition with Dnmt3a/3b. Reason: Neri et al. (2013) show a mouse Dnmt3l-PRC2 interaction that keeps bivalent promoters hypomethylated. The colocalizes_with qualifier is appropriate since DNMT3L is not a PRC2 subunit. This ESC-specific role is peripheral to its core function as a DNMT3 activator. Supporting Evidence: PMID:24074865 We demonstrate that Dnmt3L interacts with the Polycomb PRC2 complex in competition with the DNA methyltransferases Dnmt3a and Dnmt3b to maintain low methylation levels at the H3K27me3 regions.
GO:0035098 ESC/E(Z) complex	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Colocalizes_with ESC/E(Z) (PRC2) complex, transferred from mouse. In mouse ESCs Dnmt3l interacts with PRC2 (EZH2) in competition with Dnmt3a/3b. Reason: Neri et al. (2013) show a mouse Dnmt3l-PRC2 interaction that keeps bivalent promoters hypomethylated. The colocalizes_with qualifier is appropriate since DNMT3L is not a PRC2 subunit. This ESC-specific role is peripheral to its core function as a DNMT3 activator. Supporting Evidence: PMID:24074865 We demonstrate that Dnmt3L interacts with the Polycomb PRC2 complex in competition with the DNA methyltransferases Dnmt3a and Dnmt3b to maintain low methylation levels at the H3K27me3 regions.
GO:0045814 negative regulation of gene expression, epigenetic	IDA PMID:12202768 Dnmt3L is a transcriptional repressor that recruits histone ...	ACCEPT	Summary: Human DNMT3L represses transcription in an HDAC1-dependent, trichostatin-sensitive way (IDA), and more broadly silences genes epigenetically by directing de novo DNA methylation. Reason: Both the HDAC-dependent repression shown in the source paper and DNMT3L-dependent establishment of silencing methylation at imprinted loci fall under epigenetic negative regulation of gene expression. Supporting Evidence: PMID:12202768 We find that Dnmt3L can repress transcription and that this repression is dependent on HDAC1 and is relieved by treatment with the HDAC inhibitor trichostatin A. PMID:11719692 Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated.
GO:0045892 negative regulation of DNA-templated transcription	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA from node PTN002747444 (DNMT3 clade, donor DNMT3A). DNMT3L itself represses transcription when tethered to DNA, dependent on HDAC1. Reason: Supported for DNMT3L by direct repression assays (Deplus et al. 2002), so the IBA placement is consistent with the target's own data. The physiologically relevant repression is epigenetic (captured by negative regulation of gene expression, epigenetic), so this broader transcriptional term is kept as non-core. Supporting Evidence: PMID:12202768 We find that Dnmt3L can repress transcription and that this repression is dependent on HDAC1 and is relieved by treatment with the HDAC inhibitor trichostatin A.
GO:0048863 stem cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Stem cell differentiation transferred from mouse: Dnmt3l is required for ESC differentiation into primordial germ cells via Rhox5 activation. Reason: Supported by mouse ESC experiments (Neri et al. 2013), but this is a downstream developmental consequence of DNMT3L regulating promoter methylation, so it is kept as non-core. Supporting Evidence: PMID:24074865 Dnmt3L is required for the differentiation of ESCs into primordial germ cells (PGCs) through the activation of the homeotic gene Rhox5.
GO:0048863 stem cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Stem cell differentiation transferred from mouse: Dnmt3l is required for ESC differentiation into primordial germ cells via Rhox5 activation. Reason: Supported by mouse ESC experiments (Neri et al. 2013), but this is a downstream developmental consequence of DNMT3L regulating promoter methylation, so it is kept as non-core. Supporting Evidence: PMID:24074865 Dnmt3L is required for the differentiation of ESCs into primordial germ cells (PGCs) through the activation of the homeotic gene Rhox5.
GO:0071514 genomic imprinting	IEA GO_REF:0000107	ACCEPT	Summary: DNMT3L is required for establishing maternal (and paternal) methylation imprints in the germline, acting with DNMT3A. Reason: Mouse Dnmt3l knockouts fail to methylate maternally imprinted sequences in oocytes, causing biallelic expression in offspring. DNMT3L contributes directly by activating DNMT3A and reading H3K4me0 at target regions. The transfer is to a 1:1 ortholog in PANTHER subfamily SF13. Supporting Evidence: PMID:11719692 Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated. PMID:11934864 is essential for the establishment of maternal methylation imprints and appropriate expression of maternally imprinted genes. PMID:17713477 the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase.
GO:0071514 genomic imprinting	ISS GO_REF:0000024	ACCEPT	Summary: DNMT3L is required for establishing maternal (and paternal) methylation imprints in the germline, acting with DNMT3A. Reason: Mouse Dnmt3l knockouts fail to methylate maternally imprinted sequences in oocytes, causing biallelic expression in offspring. DNMT3L contributes directly by activating DNMT3A and reading H3K4me0 at target regions. The transfer is to a 1:1 ortholog in PANTHER subfamily SF13. Supporting Evidence: PMID:11719692 Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated. PMID:11934864 is essential for the establishment of maternal methylation imprints and appropriate expression of maternally imprinted genes. PMID:17713477 the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase.
GO:0090310 negative regulation of DNA methylation-dependent heterochromatin formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Negative regulation of DNA methylation-dependent heterochromatin formation, transferred from mouse. In ESCs Dnmt3l keeps bivalent promoters hypomethylated by competing with Dnmt3a/3b for PRC2. Reason: Neri et al. (2013) directly support DNMT3L acting as a negative regulator of methylation at bivalent promoters in mouse ESCs. This is a context-specific role, opposite to its main activating function, so it is kept as non-core. Supporting Evidence: PMID:24074865 Dnmt3L is a positive regulator of methylation at the gene bodies of housekeeping genes and, more surprisingly, is also a negative regulator of methylation at promoters of bivalent genes. PMID:24074865 We demonstrate that Dnmt3L interacts with the Polycomb PRC2 complex in competition with the DNA methyltransferases Dnmt3a and Dnmt3b to maintain low methylation levels at the H3K27me3 regions.
GO:0090310 negative regulation of DNA methylation-dependent heterochromatin formation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Negative regulation of DNA methylation-dependent heterochromatin formation, transferred from mouse. In ESCs Dnmt3l keeps bivalent promoters hypomethylated by competing with Dnmt3a/3b for PRC2. Reason: Neri et al. (2013) directly support DNMT3L acting as a negative regulator of methylation at bivalent promoters in mouse ESCs. This is a context-specific role, opposite to its main activating function, so it is kept as non-core. Supporting Evidence: PMID:24074865 Dnmt3L is a positive regulator of methylation at the gene bodies of housekeeping genes and, more surprisingly, is also a negative regulator of methylation at promoters of bivalent genes. PMID:24074865 We demonstrate that Dnmt3L interacts with the Polycomb PRC2 complex in competition with the DNA methyltransferases Dnmt3a and Dnmt3b to maintain low methylation levels at the H3K27me3 regions.
GO:0141005 transposable element silencing by heterochromatin formation	ISS GO_REF:0000024	ACCEPT	Summary: Retrotransposon silencing in the male germline depends on DNMT3L-mediated de novo methylation (ISS from mouse). Reason: Dnmt3l deletion prevents de novo methylation of LTR and non-LTR retrotransposons in mouse prospermatogonia, which are then highly transcribed. DNMT3L is part of the methylation machinery that does the silencing. Supporting Evidence: PMID:15318244 Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes.
GO:0141196 transposable element silencing by piRNA-mediated DNA methylation	IEA GO_REF:0000107	ACCEPT	Summary: Transposable element silencing by piRNA-directed DNA methylation (from mouse). DNMT3L is part of the de novo methylation machinery recruited downstream of the piRNA pathway to young retrotransposons in fetal prospermatogonia; it interacts with SPOCD1 (by similarity). Reason: DNMT3L is the DNMT3A-activating subunit of the methylation step that piRNA-guided silencing uses, so it does part of the work of this process. Mouse genetics show retrotransposon methylation fails without it, and UniProt records a SPOCD1 interaction by similarity. Supporting Evidence: PMID:15318244 Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes. file:human/DNMT3L/DNMT3L-uniprot.txt direct (By similarity). Interacts with SPOCD1 (By similarity).
GO:1902494 catalytic complex	IPI PMID:25383530 Structural insight into autoinhibition and histone H3-induce...	MODIFY	Summary: Part_of catalytic complex from DNMT3A-DNMT3L and DNMT3B-DNMT3L structures. Correct but very general; the complex is a DNA methyltransferase heterotetramer. Reason: DNMT3L is a non-catalytic subunit of the DNMT3A-DNMT3L and DNMT3B-DNMT3L heterotetramers, which methylate DNA. The is_a descendant DNA methyltransferase complex (GO:0140020) is the precise term. Proposed replacements: DNA methyltransferase complex Supporting Evidence: PMID:25383530 We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. PMID:32083663 The two recombinant proteins interacted with each other and formed a stable complex at a one-to-one ratio and with a molecular mass of ∼110 kDa, suggesting that DNMT3B–3L complex is a heterotetramer in solution file:human/DNMT3L/DNMT3L-uniprot.txt composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-
GO:1902494 catalytic complex	IPI PMID:32083663 Structural insights into CpG-specific DNA methylation by hum...	MODIFY	Summary: Part_of catalytic complex from DNMT3A-DNMT3L and DNMT3B-DNMT3L structures. Correct but very general; the complex is a DNA methyltransferase heterotetramer. Reason: DNMT3L is a non-catalytic subunit of the DNMT3A-DNMT3L and DNMT3B-DNMT3L heterotetramers, which methylate DNA. The is_a descendant DNA methyltransferase complex (GO:0140020) is the precise term. Proposed replacements: DNA methyltransferase complex Supporting Evidence: PMID:25383530 We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. PMID:32083663 The two recombinant proteins interacted with each other and formed a stable complex at a one-to-one ratio and with a molecular mass of ∼110 kDa, suggesting that DNMT3B–3L complex is a heterotetramer in solution file:human/DNMT3L/DNMT3L-uniprot.txt composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-
GO:0140006 histone H3 reader activity	IDA PMID:17687327 DNMT3L connects unmethylated lysine 4 of histone H3 to de no...	NEW	Summary: DNMT3L's N-terminal ADD (cysteine-rich, PHD-like) domain directly binds the unmodified N-terminal tail of histone H3; binding is abolished by H3K4 methylation. Reason: Human DNMT3L-H3 tail co-crystal structure, peptide-binding assays and binding-site mutagenesis directly establish that DNMT3L recognizes H3 unmethylated at K4. GO:0140006 explicitly covers readers of unmodified H3. This is a molecular function the protein itself performs, not a process it is required for, and no existing annotation captures it. Supporting Evidence: PMID:17687327 Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. PMID:17687327 Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. PMID:17713477 the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase.

Gene Description

Existing Annotations Review

Core Functions

Non-catalytic activator subunit of the de novo DNA methyltransferases DNMT3A and DNMT3B. It binds their catalytic domains to form heterotetramers and stimulates methylation of genomic DNA, establishing germline imprints and silencing retrotransposons.

Chromatin reader: the ADD domain binds the N-terminal tail of histone H3 when lysine 4 is unmethylated, directing DNMT3-dependent de novo methylation to H3K4me0 chromatin.

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