JMJD-3.1 is a JmjC domain-containing lysine-specific demethylase belonging to the UTX/KDM6 family that specifically demethylates H3K27me2/me3, marks associated with transcriptional repression. The enzyme requires Fe(II) as a cofactor for its dioxygenase activity. JMJD-3.1 functions in the nucleus where it removes repressive H3K27 methylation marks at specific loci to enable gene activation. Unlike the related UTX-1 which is the dominant global H3K27 demethylase during development, JMJD-3.1 acts more locus-specifically and contributes primarily to stress response pathways including the mitochondrial unfolded protein response (UPRmt) and heat shock response. It is required for the robust transdifferentiation of the Y rectal epithelial cell into the PDA motor neuron during larval development. Overexpression of jmjd-3.1 extends lifespan in a manner dependent on UPRmt components (ATFS-1, UBL-5, CLPP-1).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0010468 regulation of gene expression | IBA GO_REF:0000033 | ACCEPT | Summary: JMJD-3.1 regulates gene expression by removing repressive H3K27me2/me3 marks, thereby enabling transcriptional activation. This is well-supported by studies showing jmjd-3.1 is required for stress-induced gene expression programs (UPRmt, HSR) and for gene activation during transdifferentiation (PMID:25124442, PMID:27133168). Reason: The IBA annotation accurately captures that jmjd-3.1 regulates gene expression. As an H3K27 demethylase, its core function is to remove repressive chromatin marks and enable transcriptional activation of specific gene sets. This is a parent term to more specific processes and is appropriate for the phylogenetic inference. Supporting Evidence: PMID:25124442 a conserved H3K27me3/me2 demethylase, JMJD-3.1, and the H3K4 methyltransferase Set1 complex cooperate to ensure invariant transdifferentiation (Td) of postmitotic Caenorhabditis elegans hindgut cells into motor neurons PMID:27133168 We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species file:worm/jmjd-3.1/jmjd-3.1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0071558 histone H3K27me2/H3K27me3 demethylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: JMJD-3.1 is a member of the UTX/KDM6 family and contains the conserved JmjC catalytic domain. Experimental evidence from PMID:17713478 and PMID:25124442 demonstrates H3K27me2/me3 demethylase activity. Mutations in catalytic residues abolish function in transdifferentiation assays (PMID:25124442). Reason: This is the core molecular function of jmjd-3.1. The IBA annotation is consistent with direct experimental evidence from IDA annotations and the known domain architecture (JmjC domain with conserved Fe-binding residues). This represents the primary enzymatic activity of the protein. Supporting Evidence: PMID:17713478 mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development PMID:25124442 a conserved H3K27me3/me2 demethylase, JMJD-3.1 |
| GO:0044666 MLL3/4 complex | IBA GO_REF:0000033 | UNDECIDED | Summary: The IBA annotation infers MLL3/4 complex membership based on orthology to mammalian JMJD3/KDM6B. However, in C. elegans, UTX-1 (not jmjd-3.1) has been shown to associate with SET-16/MLL-like complexes. The literature explicitly notes that jmjd-3.1 partners are not well established and it may act more locus-specifically rather than as part of large chromatin assemblies. Reason: While mammalian JMJD3/KDM6B is associated with MLL3/4 complexes, direct evidence for C. elegans jmjd-3.1 membership in an equivalent complex is lacking. The literature (Vandamme et al. 2012) specifically found UTX-1 in complex with SET-16 but did not identify jmjd-3.1 complex partners. The phylogenetic inference may not hold in this case given the functional divergence between UTX-1 and JMJD-3 paralogs in C. elegans. More biochemical evidence is needed to confirm or refute this annotation. Supporting Evidence: PMID:22570628 Biochemical analysis identified UTX-1 as a component of a complex that includes SET-16(MLL) |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | REMOVE | Summary: This annotation suggests jmjd-3.1 has sequence-specific DNA binding activity at Pol II regulatory regions. However, jmjd-3.1 is recruited to chromatin through protein-protein interactions (e.g., with transcription factors like UNC-3) rather than through intrinsic sequence-specific DNA binding. The protein lacks recognizable DNA-binding domains. Reason: JMJD-3.1 does not contain canonical sequence-specific DNA-binding domains. While it functions at regulatory regions to demethylate H3K27, it is recruited through interactions with transcription factors (e.g., UNC-3 as shown in PMID:25124442) rather than through direct sequence-specific DNA recognition. The chromatin DNA binding annotation (GO:0031490) is more appropriate. Supporting Evidence: PMID:25124442 phase-specific interactions with transcription factors that have conserved roles in cell plasticity and terminal fate selection |
| GO:0031490 chromatin DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: JMJD-3.1 functions at chromatin where it demethylates H3K27. The protein requires recognition of the H3 tail for its function (PMID:25124442). This general chromatin binding activity is consistent with its role as a histone demethylase. Reason: As a histone demethylase that acts on chromatin-bound histones, jmjd-3.1 must bind to chromatin to carry out its function. The annotation is appropriate and consistent with the enzymatic mechanism. UniProt also notes a region required for binding and function (residues 418-759). Supporting Evidence: PMID:25124442 robust conversion requires stepwise histone-modifying activities, functionally partitioned into discrete phases of Td |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization is well-established for jmjd-3.1 by direct experimental evidence. The protein contains a region required for nuclear localization (residues 369-417) and overexpressed jmjd-3.1::mCherry shows diffuse nuclear localization. Reason: This IEA annotation is correct and supported by direct experimental evidence (IDA from PMID:25124442). Nuclear localization is essential for jmjd-3.1 function as a chromatin modifier. Supporting Evidence: PMID:25124442 functionally partitioned into discrete phases of Td through nuclear degradation of JMJD-3.1 |
| GO:0006325 chromatin organization | IEA GO_REF:0000043 | ACCEPT | Summary: As an H3K27 demethylase, jmjd-3.1 directly modifies chromatin structure by removing methyl groups from histones. This alters the chromatin state from repressive to permissive for transcription. Reason: H3K27 demethylation directly affects chromatin organization by removing repressive marks and enabling chromatin state transitions. This is a core aspect of jmjd-3.1 function as a histone-modifying enzyme. Supporting Evidence: PMID:25124442 Sequential histone-modifying activities determine the robustness of transdifferentiation |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000120 | MODIFY | Summary: While jmjd-3.1 modifies chromatin through histone demethylation, chromatin remodeling (GO:0006338) specifically refers to ATP-dependent alteration of nucleosome structure. Histone demethylation is a distinct process from ATP-dependent chromatin remodeling. Reason: Chromatin remodeling in GO specifically refers to ATP-dependent nucleosome repositioning or eviction. JMJD-3.1 is not an ATP-dependent chromatin remodeler but rather a covalent histone modifier. The more appropriate process term is 'chromatin organization' (GO:0006325); the demethylation itself is captured by the MF histone H3K27me2/H3K27me3 demethylase activity (GO:0071558), since GO obsoleted the process term histone H3-K27 demethylation (GO:0071557) as a molecular function. Proposed replacements: chromatin organization |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | ACCEPT | Summary: JMJD-3.1 catalyzes an oxidative demethylation reaction using Fe(II) and 2-oxoglutarate as cofactors, making it technically an oxidoreductase. However, this is a very general term. Reason: As a JmjC domain dioxygenase, jmjd-3.1 does have oxidoreductase activity. While this is a broad parent term, it is technically correct for an IEA annotation derived from keyword mapping. The more specific H3K27me2/me3 demethylase activity annotation captures the precise function. |
| GO:0032452 histone demethylase activity | IEA GO_REF:0000117 | ACCEPT | Summary: JMJD-3.1 is a bona fide histone demethylase with specificity for H3K27me2/me3. This parent term is appropriate. Reason: This is a correct parent term for the more specific H3K27me2/me3 demethylase activity. The IEA annotation is consistent with experimental evidence. Supporting Evidence: PMID:17713478 UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: JMJD-3.1 binds Fe(II) as a required cofactor for its dioxygenase activity. The JmjC domain contains conserved histidine and glutamate residues (H811, E813, H891) that coordinate Fe(II). Additionally, the C-terminal region contains a zinc-binding site (C998, C1001, C1025, C1028). Reason: Metal ion binding is essential for jmjd-3.1 function. UniProt annotation confirms Fe(II) as cofactor and zinc binding at the C-terminus. While a more specific term like 'iron ion binding' could be used, this general annotation is appropriate for an IEA. |
| GO:0051213 dioxygenase activity | IEA GO_REF:0000043 | ACCEPT | Summary: The JmjC domain of jmjd-3.1 catalyzes an Fe(II)/2-oxoglutarate-dependent dioxygenase reaction that demethylates H3K27. This is the mechanistic basis for histone demethylation. Reason: JmjC domain histone demethylases function as dioxygenases, using molecular oxygen and 2-oxoglutarate in a hydroxylation reaction that leads to demethylation. This is biochemically accurate for the enzymatic mechanism. |
| GO:0005634 nucleus | IDA PMID:25124442 Transdifferentiation. Sequential histone-modifying activitie... | ACCEPT | Summary: Direct observation of jmjd-3.1 localization using tagged constructs showed diffuse nuclear localization. The protein contains a region (residues 369-417) required for nuclear localization. Reason: Nuclear localization is directly demonstrated by imaging of tagged jmjd-3.1 constructs. This is essential for its function as a chromatin modifier acting on nuclear histones. Supporting Evidence: PMID:25124442 functionally partitioned into discrete phases of Td through nuclear degradation of JMJD-3.1 |
| GO:0060290 transdifferentiation | IMP PMID:25124442 Transdifferentiation. Sequential histone-modifying activitie... | ACCEPT | Summary: JMJD-3.1 is required for the robust transdifferentiation of the Y rectal epithelial cell into the PDA motor neuron. Loss of function or catalytic dead mutations disrupt this invariant cell fate conversion. The demethylase activity and H3 tail recognition are required for this function. Reason: This is one of the best-characterized biological processes for jmjd-3.1 in C. elegans. The study demonstrates cell-autonomous requirement and dependence on catalytic activity. However, this represents a specific developmental role rather than the core molecular function of the protein. Supporting Evidence: PMID:25124442 a conserved H3K27me3/me2 demethylase, JMJD-3.1, and the H3K4 methyltransferase Set1 complex cooperate to ensure invariant transdifferentiation (Td) of postmitotic Caenorhabditis elegans hindgut cells into motor neurons PMID:25124442 robust conversion requires stepwise histone-modifying activities, functionally partitioned into discrete phases of Td through nuclear degradation of JMJD-3.1 |
| GO:0071558 histone H3K27me2/H3K27me3 demethylase activity | IDA PMID:25124442 Transdifferentiation. Sequential histone-modifying activitie... | ACCEPT | Summary: The study demonstrates that jmjd-3.1 functions as an H3K27me3/me2 demethylase in the context of transdifferentiation. Mutations in catalytic residues (G888E, S903F) abolish demethylase activity and function. Reason: Direct experimental evidence demonstrates H3K27 demethylase activity through functional assays showing that catalytic domain mutations abolish the ability to promote transdifferentiation and demethylate H3K27. Supporting Evidence: PMID:25124442 a conserved H3K27me3/me2 demethylase, JMJD-3.1 |
| GO:0071558 histone H3K27me2/H3K27me3 demethylase activity | IMP PMID:25124442 Transdifferentiation. Sequential histone-modifying activitie... | ACCEPT | Summary: Mutant phenotype analysis shows that loss of jmjd-3.1 or catalytic dead mutations result in failure of transdifferentiation and correlate with H3K27 methylation status. Reason: IMP evidence from mutant analysis supports the demethylase activity assignment. Mutations in the JmjC catalytic domain residues (HME->TMG at 811-813, G888E, S903F) disrupt function consistent with loss of demethylase activity. Supporting Evidence: PMID:25124442 robust conversion requires stepwise histone-modifying activities, functionally partitioned into discrete phases of Td through nuclear degradation of JMJD-3.1 |
| GO:0071558 histone H3K27me2/H3K27me3 demethylase activity | IDA PMID:17713478 UTX and JMJD3 are histone H3K27 demethylases involved in HOX... | ACCEPT | Summary: This foundational study identified jmjd-3.1 (F18E9.5) as a C. elegans ortholog of human JMJD3 and demonstrated that mutation or RNAi knockdown causes developmental defects consistent with loss of H3K27 demethylase function. Reason: This is the original study identifying jmjd-3.1 as an H3K27 demethylase ortholog. While the biochemical demonstration was primarily done with human JMJD3, the C. elegans ortholog showed functional conservation in gonad development assays. Supporting Evidence: PMID:17713478 mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development |
| GO:0034620 cellular response to unfolded protein | IMP PMID:27133168 Two Conserved Histone Demethylases Regulate Mitochondrial St... | NEW | Summary: JMJD-3.1 is necessary and sufficient for activation of the mitochondrial unfolded protein response (UPRmt). Overexpression of jmjd-3.1 induces UPRmt gene expression including hsp-6, dve-1, and spg-7. The lifespan extension by jmjd-3.1 overexpression depends on UPRmt components ATFS-1, UBL-5, and CLPP-1. Reason: The role of jmjd-3.1 in UPRmt activation is a major characterized function not captured in the current annotation set. Reduction of function of the demethylases potently suppresses longevity and UPRmt induction. Supporting Evidence: PMID:27133168 Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner |
| GO:0008340 determination of adult lifespan | IMP PMID:27133168 Two Conserved Histone Demethylases Regulate Mitochondrial St... | NEW | Summary: JMJD-3.1 regulates lifespan in C. elegans. Overexpression extends lifespan while knockdown reduces lifespan and suppresses mitochondrial stress-induced longevity. This is an evolutionarily conserved role as mammalian orthologs also regulate longevity. Reason: Lifespan regulation is a well-documented phenotype for jmjd-3.1, mediated through its effects on stress response gene expression and proteostasis. Supporting Evidence: PMID:27133168 We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species PMID:27133168 Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner |
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Download this section (compressed HTML)Q: Does jmjd-3.1 function as part of a larger chromatin-modifying complex in C. elegans, similar to mammalian JMJD3 in MLL3/4 complexes? While UTX-1 associates with SET-16/MLL-like complexes, jmjd-3.1 protein partners remain poorly defined. Understanding whether it acts alone or in a complex would clarify its recruitment mechanism.
Q: What is the genomic targeting mechanism for jmjd-3.1 at stress-responsive loci? JMJD-3.1 appears to act at specific loci rather than globally. The interaction with UNC-3 provides one example, but genome-wide ChIP studies would reveal the full scope of its targets.
Q: How do the three JMJD3 paralogs (jmjd-3.1, jmjd-3.2, jmjd-3.3) partition their functions? Triple deletion shows no additional phenotypes beyond jmjd-3.1 single mutants, suggesting potential redundancy, but individual paralogs may have distinct stress-specific or tissue-specific roles.
Experiment: ChIP-seq for jmjd-3.1 under basal and stress conditions to map genome-wide binding sites and correlate with H3K27me3 changes
Experiment: Co-immunoprecipitation/mass spectrometry of jmjd-3.1 to identify protein interaction partners and potential complex membership
Experiment: Single-cell transcriptomics during Y-to-PDA transdifferentiation in jmjd-3.1 mutants to identify specific gene targets deregulated during cell fate conversion
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