EGR2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: EGR2 is a well-established C2H2 zinc finger transcription factor that binds specific GC-rich cis-regulatory sequences in RNA pol II-transcribed genes. IBA annotation supported by phylogenetic inference across the EGR/Krox/Sp family is consistent with extensive experimental evidence (PMID:17717711, PMID:12687019, PMID:28473536). Reason: Core molecular function of EGR2 as a sequence-specific DNA-binding TF. EGR2 binds GC-rich EGR consensus sites (e.g. 5'-GCGGGGGCG-3') via its zinc fingers. This IBA annotation is well supported by direct experimental evidence from multiple studies. Supporting Evidence: PMID:9537424 Egr2, (also known as Krox20) ... encoding a protein that binds DNA in a sequence-specific manner and acts as a transcription factor PMID:14532282 Krox20, a zinc finger transcription factor required for Schwann cell differentiation
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	Summary: EGR2/Krox-20 is a bona fide DNA-binding transcription factor that activates RNA polymerase II-dependent transcription of target genes including myelin genes and HOX genes. IBA annotation well supported phylogenetically and experimentally. Reason: Core molecular function. EGR2 directly binds DNA and activates pol II transcription. This is the primary molecular function of EGR2 and is supported by IDA evidence from PMID:17717711 and PMID:12687019, as well as the TFClass database annotation. Supporting Evidence: PMID:17717711 Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies PMID:14532282 Krox20, a zinc finger transcription factor required for Schwann cell differentiation, ... showed a strong requirement for functional HCF-1 to activate transcription
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: EGR2 functions as a nuclear transcription factor. IBA annotation is fully consistent with UniProt subcellular localization and all functional evidence placing EGR2 in the nucleus where it binds DNA and regulates transcription. Reason: Core localization. EGR2 is a nuclear TF. UniProt states "Nucleus" as subcellular location. All evidence from functional studies and the Reactome pathway annotations place EGR2 in the nucleoplasm. Supporting Evidence: PMID:14532282 Krox20, a zinc finger transcription factor required for Schwann cell differentiation
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: EGR2 is directly involved in regulation of RNA pol II transcription. This IBA annotation at a general level captures the core biological process role of EGR2 as a transcription factor. More specific annotations (positive regulation) are also present. Reason: Core biological process. EGR2 regulates pol II transcription of myelin genes (MPZ, PMP22, GJB1, MAG), HOX genes, BNIP3L/BAK (PMID:12687019), and lipid biosynthesis genes. This broad term is appropriate for the IBA level. Supporting Evidence: PMID:12687019 EGR2 could induce apoptosis in a large proportion of these lines ... EGR2 directly transactivates expression of BNIP3L and BAK
GO:0003677 DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for DNA binding based on UniProt keyword mapping. EGR2 has three C2H2 zinc finger domains that mediate sequence-specific DNA binding. This is a broad parent term of the more specific cis-regulatory region binding terms. Reason: Correct but general. More specific terms (GO:0000978, GO:1990837) are also annotated. This IEA is acceptable as a broader annotation consistent with the more specific experimental evidence. Supporting Evidence: PMID:9537424 encoding a protein that binds DNA in a sequence-specific manner
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nucleus based on combined automated methods including ortholog mapping from mouse Egr2. Consistent with all other evidence. Reason: Correct. Duplicates the IBA annotation but with different evidence code. EGR2 is a nuclear protein.
GO:0005654 nucleoplasm	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for nucleoplasm from ARBA machine learning. Consistent with EGR2 being a nuclear transcription factor. Also supported by multiple Reactome TAS annotations for nucleoplasm. Reason: Correct. As a nuclear transcription factor, EGR2 functions in the nucleoplasm.
GO:0008270 zinc ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation based on UniProt keyword "Zinc". EGR2 contains three C2H2-type zinc finger domains (residues 340-364, 370-392, 398-420) that coordinate zinc ions for structural integrity and DNA binding. Reason: Correct. The three C2H2 zinc fingers are structurally essential for EGR2 DNA-binding function. Disease-causing mutations cluster in these zinc finger domains.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation based on UniProt keyword "Transferase". This reflects the E3 SUMO ligase activity of EGR2, which catalyzes transfer of SUMO1 to NAB1/NAB2 (PMID:21836637). The term is very broad. Reason: Technically correct as a parent term of SUMO ligase activity (GO:0061665). The SUMO transferase activity is a child of transferase activity. While broad, this IEA mapping from the Transferase keyword is acceptable. Supporting Evidence: PMID:21836637 we show that Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation based on UniProt keyword "Metal-binding". Broad parent of zinc ion binding. Reason: Correct but very general. The more specific GO:0008270 (zinc ion binding) is also annotated. Acceptable as an IEA parent annotation.
GO:0000976 transcription cis-regulatory region binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara ortholog transfer (from mouse Egr2). EGR2 binds cis-regulatory regions in target gene promoters and enhancers. Consistent with more specific annotations. Reason: Correct. Parent term of the more specific GO:0000978. EGR2 binds cis-regulatory elements of myelin genes, HOX genes, and other targets.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. Duplicates the IBA annotation. Consistent with experimental evidence. Reason: Correct. Duplicates IBA and IDA annotations for the same term. Acceptable.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. Duplicates the IBA and IDA annotations for this core function. Reason: Correct. Same core function captured by higher-quality evidence codes.
GO:0003682 chromatin binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. EGR2 binds chromatin at specific regulatory elements. This is consistent with its role as a transcription factor that binds DNA in a chromatin context. Reason: Reasonable. As a TF that binds cis-regulatory elements in vivo, EGR2 necessarily interacts with chromatin. Also supported by ISS annotation from the same term.
GO:0003700 DNA-binding transcription factor activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. Parent term of the more specific pol II-specific annotation. Consistent with all evidence. Reason: Correct. Broader parent of GO:0000981. Also annotated with IDA (PMID:14532282).
GO:0005737 cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara for cytoplasmic localization. EGR2 is primarily nuclear, but some evidence from mouse orthologs suggests transient cytoplasmic presence, possibly related to nuclear export. UniProt annotates nuclear export for the mouse ortholog. Reason: EGR2 is primarily a nuclear protein. Cytoplasmic localization may reflect transient shuttling or the protein before nuclear import, but this is not the primary site of function. Keeping as non-core.
GO:0006611 protein export from nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara for nuclear export. This is transferred from mouse Egr2 where there is ISS-level evidence. Nuclear export may relate to regulation of EGR2 activity or turnover. Reason: Not a core function. EGR2 activity is fundamentally nuclear. Nuclear export may be a regulatory mechanism but is not well characterized for human EGR2. Keeping as non-core.
GO:0014040 positive regulation of Schwann cell differentiation	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. EGR2 is a master regulator of Schwann cell myelination and promotes Schwann cell differentiation to the myelinating state. This is one of the best-characterized functions of EGR2. Reason: Core biological process. EGR2/Krox-20 knockout mice show a block in Schwann cell differentiation. EGR2 mutations in humans cause demyelinating neuropathies. Also supported by ISS annotation. Supporting Evidence: PMID:9537424 Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS). Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage
GO:0016925 protein sumoylation	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from combined automated methods. EGR2 functions as an E3 SUMO ligase for NAB1/NAB2 coregulators (PMID:21836637). The protein sumoylation process annotation is consistent with this enzymatic activity. Reason: Correct. EGR2 catalyzes SUMO1 conjugation to NAB proteins. This is an experimentally validated function (PMID:21836637) and is appropriately reflected in this process annotation. Supporting Evidence: PMID:21836637 Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins--and that Nab sumoylation negatively modulates Krox20 transcriptional activity in vivo
GO:0021612 facial nerve structural organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara. EGR2 is expressed in rhombomeres 3 and 5 during hindbrain development, and Egr2 knockout mice show defects in cranial nerve organization including the facial nerve. Reason: Developmental role. EGR2 regulates hindbrain segmentation and thereby influences cranial nerve patterning, including the facial nerve. This is a downstream developmental consequence rather than a direct molecular function. Keeping as non-core. Supporting Evidence: PMID:17717711 respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations
GO:0021659 rhombomere 3 structural organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara. EGR2/Krox-20 is specifically expressed in rhombomeres 3 and 5 and is required for their proper specification. This is a core developmental function of EGR2. Reason: Important developmental function. EGR2 specifies odd rhombomeres by controlling HOX gene expression. This is a well-established role from Egr2 knockout studies but represents a developmental consequence of its TF activity rather than a direct molecular function. Keeping as non-core because it is a downstream developmental process.
GO:0021665 rhombomere 5 structural organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara. Like rhombomere 3, EGR2 is also required for rhombomere 5 organization during hindbrain development. Reason: Same rationale as rhombomere 3 organization. Well-established developmental role but downstream of core TF activity.
GO:0031643 positive regulation of myelination	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. EGR2 is a master positive regulator of peripheral myelination, activating myelin gene expression. Reason: Core biological process function. EGR2 is the key transcription factor driving peripheral myelination. Its loss causes demyelinating neuropathies. Also supported by ISS annotation. Supporting Evidence: PMID:9537424 Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system
GO:0035904 aorta development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara. EGR2 has been implicated in vascular smooth muscle and aorta development in mouse knockout studies, but this is not a well-characterized function for human EGR2. Reason: Peripheral function. EGR2 expression is induced by growth factors and may play roles in multiple tissues including vasculature, but this is not a core function. Mouse knockout evidence is the primary support. Keeping as non-core.
GO:0043565 sequence-specific DNA binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. EGR2 binds specific GC-rich DNA consensus sequences through its zinc finger domains. Reason: Correct. Parent of more specific terms. Also annotated with IDA (PMID:17717711).
GO:0045444 fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara. Mouse Egr2 has been implicated in adipogenesis, possibly through regulation of CEBPB. This is a secondary function for the human ortholog. Reason: Peripheral function. While EGR2 may play a role in adipocyte differentiation (UniProt mentions this by similarity), this is not a core function. The primary roles are in myelination and hindbrain development.
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. EGR2 positively regulates transcription of target genes. Consistent with its role as a transcriptional activator. Reason: Correct. EGR2 is primarily a transcriptional activator. This is a broad parent of the more specific pol II-specific positive regulation terms.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. EGR2 interacts with other transcription factors and coregulators, including HCFC1 (PMID:14532282), NAB1/NAB2, and SOX10. Reason: Correct. EGR2 binds to other TF-related proteins. HCFC1 interaction is experimentally validated (PMID:14532282). NAB1/NAB2 interactions are central to EGR2 function. Supporting Evidence: PMID:14532282 Krox20, a zinc finger transcription factor required for Schwann cell differentiation, and E2F4, a cell cycle regulator, showed a strong requirement for functional HCF-1 to activate transcription
GO:0061665 SUMO ligase activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara. EGR2 has experimentally demonstrated E3 SUMO ligase activity (PMID:21836637), catalyzing SUMO1 conjugation to NAB coregulators. Reason: Correct. SUMO ligase activity is experimentally validated. EGR2 interacts with UBC9 and facilitates SUMO transfer to NAB1/NAB2. Also annotated with ISS evidence. Supporting Evidence: PMID:21836637 Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins
GO:1990837 sequence-specific double-stranded DNA binding	IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ...	ACCEPT	Summary: IDA annotation from a systematic high-throughput SELEX study (Yin et al. 2017) that characterized DNA binding specificities of 542 human TFs. EGR2 was among the TFs analyzed for binding to both unmethylated and CpG-methylated DNA. Reason: Well-supported by high-throughput systematic analysis of TF binding specificities. EGR2 binds dsDNA in a sequence-specific manner through its C2H2 zinc fingers. The SELEX assay directly measures dsDNA binding. Supporting Evidence: PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2 (P08152). EGR2 positively regulates pol II transcription. Also supported by IDA annotations from PMID:17717711 and PMID:12687019. Reason: Core function. ISS is consistent with IDA evidence from the same gene product.
GO:0014037 Schwann cell differentiation	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2. EGR2 is essential for Schwann cell differentiation from the premyelinating to myelinating state. Reason: Core biological process. Egr2 knockout mice show a complete block in Schwann cell differentiation. Human EGR2 mutations cause demyelinating neuropathies confirming this conserved function. Supporting Evidence: PMID:9537424 Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage
GO:0014040 positive regulation of Schwann cell differentiation	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2. EGR2 positively drives Schwann cell differentiation toward the myelinating phenotype. Reason: Core function. Duplicates the IEA annotation with higher-quality ISS evidence.
GO:0021612 facial nerve structural organization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse Egr2. EGR2 is required for proper facial nerve patterning during hindbrain development. Reason: Developmental consequence. Consistent with IEA annotation. Cranial nerve dysfunction is a clinical feature of EGR2 mutations (PMID:17717711). Supporting Evidence: PMID:17717711 respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations
GO:0021659 rhombomere 3 structural organization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse Egr2. Egr2 is expressed in r3 and r5 and is required for their specification. Reason: Developmental process. Duplicates IEA annotation with higher-quality ISS evidence. EGR2 specifies rhombomere identity through HOX gene regulation.
GO:0021665 rhombomere 5 structural organization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse Egr2. Same rationale as rhombomere 3. Reason: Developmental process. Consistent with EGR2 expression in r5 and its role in hindbrain segmentation.
GO:0031643 positive regulation of myelination	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2. EGR2 is the master positive regulator of peripheral myelination. Reason: Core function. Duplicates IEA annotation with higher-quality ISS evidence.
GO:0035914 skeletal muscle cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse Egr2. There is some evidence from mouse studies for EGR2 involvement in jaw opener musculature development, but this is not well characterized for human EGR2. Reason: Peripheral function. UniProt mentions a role in jaw opener musculature development by similarity. This is not a core function and evidence in human is limited.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IDA PMID:17717711 Functional, histopathologic and natural history study of neu...	ACCEPT	Summary: IDA annotation based on Szigeti et al. 2007, which characterized EGR2 mutations functionally, demonstrating that wild-type EGR2 has DNA-binding transcription factor activity and that disease mutations abolish this activity. Reason: Core molecular function supported by direct assay. The R359W and E412K mutations caused loss of DNA binding and transactivation activity, confirming WT EGR2 has this function. Supporting Evidence: PMID:17717711 Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies
GO:0043565 sequence-specific DNA binding	IDA PMID:17717711 Functional, histopathologic and natural history study of neu...	ACCEPT	Summary: IDA annotation from functional characterization of EGR2 mutations. Disease mutations in zinc finger domains abolished sequence-specific DNA binding, confirming wild-type EGR2 binds DNA in a sequence-specific manner. Reason: Core molecular function. Direct assay evidence from functional studies of disease variants.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:17717711 Functional, histopathologic and natural history study of neu...	ACCEPT	Summary: IDA annotation from functional characterization of EGR2. Wild-type EGR2 activates pol II transcription; disease mutations cause loss of transactivation activity. Reason: Core function. Disease mutations (R359W, E412K) lost transactivation activity, confirming WT EGR2 positively regulates pol II transcription.
GO:0000785 chromatin	ISA GO_REF:0000113	ACCEPT	Summary: ISA annotation from TFClass database (tfclass:2.3.1, C2H2 zinc finger factors). As a DNA-binding transcription factor, EGR2 localizes to chromatin at its target sites. Reason: Reasonable. TF annotation from TFClass. EGR2 binds to chromatin at cis-regulatory elements of target genes.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	ISA GO_REF:0000113	ACCEPT	Summary: ISA annotation from TFClass database classification of EGR2 as a C2H2 zinc finger transcription factor (class 2.3.1). Reason: Core function. TFClass annotation consistent with all experimental evidence.
GO:0016925 protein sumoylation	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2. EGR2 participates in protein sumoylation as an E3 SUMO ligase for NAB1/NAB2. Reason: Correct. Experimentally validated in PMID:21836637. The ISS annotation from mouse is consistent with human experimental evidence. Supporting Evidence: PMID:21836637 Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins
GO:0061665 SUMO ligase activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2. EGR2 has E3 SUMO ligase activity, transferring SUMO1 to NAB coregulators via UBC9. Reason: Core enzymatic function. Experimentally demonstrated in PMID:21836637 using human Krox20. UniProt lists this as a confirmed activity with EC number. Supporting Evidence: PMID:21836637 we show that Krox20 functions as a SUMO ligase for its coregulators--the Nab proteins--and that Nab sumoylation negatively modulates Krox20 transcriptional activity in vivo
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA PMID:12687019 EGR2 induces apoptosis in various cancer cell lines by direc...	ACCEPT	Summary: IDA annotation from Unoki and Nakamura 2003, which showed EGR2 directly binds promoter regions of BNIP3L and BAK to transactivate their expression. Reason: Core function. Direct assay evidence showing EGR2 binds cis-regulatory regions of target genes and activates transcription. Supporting Evidence: PMID:12687019 EGR2 directly transactivates expression of BNIP3L and BAK
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IDA PMID:12687019 EGR2 induces apoptosis in various cancer cell lines by direc...	ACCEPT	Summary: IDA annotation for transcription activator activity from the study showing EGR2 directly transactivates BNIP3L and BAK expression. Reason: Core molecular function. This is a more specific child of GO:0000981 and accurately captures EGR2's role as a transcriptional activator. Consistent with the GO annotation guidelines for DNA-binding transcription factors. Supporting Evidence: PMID:12687019 EGR2 could induce apoptosis in a large proportion of these lines ... EGR2 directly transactivates expression of BNIP3L and BAK
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:12687019 EGR2 induces apoptosis in various cancer cell lines by direc...	ACCEPT	Summary: IDA annotation from the same study showing EGR2 positively regulates pol II transcription of BNIP3L and BAK. Reason: Core function. Direct experimental evidence for transcriptional activation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9612073	ACCEPT	Summary: TAS annotation from Reactome pathway for NGF- and MAPK-dependent EGR1, EGR2 and EGR4 expression. Places EGR2 in the nucleoplasm. Reason: Correct localization. EGR2 functions in the nucleoplasm as a transcription factor.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9612483	ACCEPT	Summary: TAS annotation from Reactome for EGR1,2,3 binding the NAB2 promoter. EGR2 binds the NAB2 promoter in the nucleoplasm. Reason: Correct. EGR2 regulates NAB2 expression as part of a negative feedback loop.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9613210	ACCEPT	Summary: TAS annotation from Reactome for EGR1, EGR2 binding the RRAD promoter. Reason: Correct localization for nucleoplasmic transcription factor activity.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9613213	ACCEPT	Summary: TAS annotation from Reactome for NAB2 and CHD4 binding and repressing EGR-mediated RRAD gene expression. Reason: Correct. EGR2-mediated transcription occurs in the nucleoplasm, and NAB2/CHD4 repress this activity.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9613476	ACCEPT	Summary: TAS annotation from Reactome for EGR2:NAB2 and CHD4 binding the ID2 and ID4 promoter regions. Reason: Correct localization for EGR2 transcriptional activity.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9613760	ACCEPT	Summary: TAS annotation from Reactome for EGR2 gene expression. Reason: Correct. EGR2 protein functions in the nucleoplasm.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9616116	ACCEPT	Summary: TAS annotation from Reactome for EGR2 and SOX10 binding the MAG gene. This represents a well-characterized myelin gene target. Reason: Correct. EGR2 cooperates with SOX10 to activate myelin gene expression in the nucleoplasm.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9618559	ACCEPT	Summary: TAS annotation from Reactome for EGR2, SOX10 and TEAD1 binding enhancers in the PMP22 gene. Reason: Correct. PMP22 is a key myelin gene regulated by EGR2.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9618725	ACCEPT	Summary: TAS annotation from Reactome for SOX10, EGR2 and NAB proteins binding the GJB1 promoter. Reason: Correct. GJB1 (connexin 32) is another myelin gene target of EGR2.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9621400	ACCEPT	Summary: TAS annotation from Reactome for EGR2 and SREBF2 dimer binding SCD5 gene. Reason: Correct. EGR2 cooperates with SREBF2 to regulate lipid biosynthesis genes important for myelin formation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9621406	ACCEPT	Summary: TAS annotation from Reactome for EGR2 and SREBF2 dimer binding CYP51A1 gene. Reason: Correct. Another lipid biosynthesis gene regulated by EGR2 for myelin formation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9621411	ACCEPT	Summary: TAS annotation from Reactome for EGR2 and SREBF2(1-484) dimer binding HMGCR gene. Reason: Correct. HMGCR encodes a cholesterol biosynthesis enzyme important for myelin lipid composition.
GO:0000976 transcription cis-regulatory region binding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2. EGR2 binds cis-regulatory regions in promoters and enhancers of target genes. Reason: Correct. Parent term of more specific DNA binding annotations.
GO:0003682 chromatin binding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from mouse Egr2. EGR2 binds chromatin at regulatory elements. Reason: Correct. EGR2 binds chromatin in the context of regulating target gene expression.
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for nuclear localization transferred from mouse Egr2. Reason: Correct. Consistent with all other evidence.
GO:0005737 cytoplasm	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for cytoplasmic localization from mouse Egr2. Reason: EGR2 is primarily nuclear. Cytoplasmic localization is likely transient.
GO:0006611 protein export from nucleus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for nuclear export from mouse Egr2. Reason: Not core. Regulatory mechanism rather than primary function.
GO:0045893 positive regulation of DNA-templated transcription	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for positive regulation of transcription from mouse Egr2. Reason: Core function. EGR2 is primarily a transcriptional activator.
GO:0005634 nucleus	IC PMID:14532282 HCF-1 functions as a coactivator for the zinc finger protein...	ACCEPT	Summary: IC (inferred by curator) annotation for nuclear localization, inferred from DNA-binding transcription factor activity (GO:0003700) demonstrated in PMID:14532282 (HCF-1 as coactivator for Krox20). Reason: Correct inference. A DNA-binding transcription factor must be in the nucleus to function. Supporting Evidence: PMID:14532282 Krox20, a zinc finger transcription factor required for Schwann cell differentiation, ... showed a strong requirement for functional HCF-1 to activate transcription
GO:0045444 fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for fat cell differentiation from mouse Egr2. Reason: Peripheral function. Not a primary role for human EGR2.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for TF binding from mouse Egr2. EGR2 interacts with other TFs and coregulators including SOX10, HCFC1, NAB1/NAB2. Reason: Correct. EGR2 interacts with multiple TF-related proteins. HCFC1 interaction validated experimentally (PMID:14532282).
GO:0031625 ubiquitin protein ligase binding	IPI PMID:19651900 The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-i...	ACCEPT	Summary: IPI annotation showing EGR2 binds the E3 ubiquitin ligase WWP2 (AIP2, UniProtKB:O00308). WWP2 ubiquitinates EGR2, leading to its proteasomal degradation, which regulates activation-induced T cell death. Reason: Experimentally validated interaction. EGR2 is a substrate of the ubiquitin ligase WWP2, and this interaction regulates EGR2 stability and consequently FasL expression in T cells. Supporting Evidence: PMID:19651900 AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death
GO:0005515 protein binding	IPI PMID:14532282 HCF-1 functions as a coactivator for the zinc finger protein...	MODIFY	Summary: IPI annotation for protein binding with HCFC1 (UniProtKB:P51610). EGR2 contains an HCF-binding motif (DHLY at residues 162-165) that mediates interaction with HCFC1, which functions as a coactivator for EGR2. Reason: The term "protein binding" (GO:0005515) is too vague and uninformative. The interaction with HCFC1 is functionally significant as a transcriptional coactivation interaction. A more specific term should be used. The RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629) already captures this type of interaction. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:14532282 HCF-1 functions as a coactivator for the zinc finger protein Krox20 ... In Krox20, the HCF-binding motif lies within the N-terminal activation domain and mutation of this sequence diminishes both transactivation and association with the HCF-1 beta-propeller
GO:0003700 DNA-binding transcription factor activity	IDA PMID:14532282 HCF-1 functions as a coactivator for the zinc finger protein...	ACCEPT	Summary: IDA annotation from Luciano and Wilson 2003. The study demonstrated EGR2/Krox20 has transcription factor activity using reporter assays and showed that HCFC1 functions as its coactivator. Reason: Core function. Direct assay evidence. While this is a parent of the more specific GO:0000981, it is acceptable as a separate IDA annotation. Supporting Evidence: PMID:14532282 Krox20, a zinc finger transcription factor required for Schwann cell differentiation, ... showed a strong requirement for functional HCF-1 to activate transcription
GO:0007420 brain development	TAS PMID:9537424 Mutations in the early growth response 2 (EGR2) gene are ass...	KEEP AS NON CORE	Summary: TAS annotation for brain development from Warner et al. 1998. EGR2 is involved in hindbrain development through its role in rhombomere specification. Egr2 knockout mice show disrupted hindbrain segmentation. Reason: Broad developmental term. EGR2 is specifically involved in hindbrain segmentation rather than general brain development. The more specific rhombomere terms capture this role better. Keeping as non-core. Supporting Evidence: PMID:9537424 Egr2(-/-) mice display disrupted hindbrain segmentation and development
GO:0007422 peripheral nervous system development	TAS PMID:9537424 Mutations in the early growth response 2 (EGR2) gene are ass...	ACCEPT	Summary: TAS annotation for PNS development from Warner et al. 1998. EGR2 is critical for peripheral nerve myelination. The paper identified EGR2 mutations in patients with hereditary myelinopathies. Reason: Core biological process. EGR2 is essential for PNS development through its role in Schwann cell myelination. Mutations cause inherited peripheral neuropathies. Supporting Evidence: PMID:9537424 Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system ... we have identified one recessive and two dominant missense mutations in EGR2 ... in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)

Gene Description

Existing Annotations Review

Core Functions

E3 SUMO ligase activity: EGR2 enables SUMO ligase activity (GO:0061665), catalyzing transfer of SUMO1 to its NAB1 and NAB2 coregulators in collaboration with the SUMO-conjugating enzyme UBC9. NAB sumoylation negatively modulates EGR2 transcriptional activity, providing a negative feedback mechanism.

Hindbrain segmentation: EGR2 is specifically expressed in and required for proper specification of rhombomeres 3 and 5 during hindbrain development, controlling expression of HOX genes (HOXB2, HOXB3, HOXA4) that specify rhombomere identity. This is a conserved developmental function.

References

Deep Research

Falcon

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