KDM4C (lysine-specific demethylase 4C, JMJD2C) is a nuclear JmjC-domain histone demethylase of the KDM4/JHDM3 family. Using Fe(II) and 2-oxoglutarate, it removes methyl groups from trimethylated lysine 9 and, less efficiently, lysine 36 of histone H3, converting H3K9me3 and H3K36me3 to lower methylation states. Besides the catalytic JmjN/JmjC module, which also carries a structural zinc site, it has PHD and double Tudor reader domains that bind methylated histone tails and are thought to target the enzyme to chromatin. It is recruited to chromatin by transcription factors such as the androgen receptor, where H3K9me3 removal derepresses target genes. KDM4A, KDM4B and KDM4C form a vertebrate-conserved KDM4 subclass with dual H3K9/H3K36 specificity. The donkey protein is a full-length KDM4C ortholog (1052 aa, 91% identical to human KDM4C) that conserves all JmjC Fe(II)-, 2-oxoglutarate- and Zn(2+)-binding residues.
Summary: KDM4C acts on histones in chromatin and is recruited to androgen receptor target genes.
Reason: TreeGrafter transfer from the KDM4 PANTHER node (PTN001322185); the donkey protein sits in the KDM4C subfamily (PTHR10694:SF104) together with human Q9H3R0, which has IDA support for chromatin association at androgen receptor target genes (PMID:17277772). Its substrates are chromatin-bound histones.
Reason: Nuclear localization follows from the JmjN-domain PROSITE rule and from its chromatin substrates, and is supported for the human ortholog in the same PANTHER subfamily.
Summary: By removing repressive H3K9me3 (and H3K36me3) marks, KDM4C directly changes chromatin state at target loci.
Reason: In current GO, chromatin remodeling is the process home for histone-modifying enzymes, and the KDM4 PANTHER node carries it. KDM4C itself catalyzes the histone modification, so this is direct participation, not a downstream effect.
Summary: KDM4C regulates transcription through histone demethylation but does not take part in RNA synthesis itself.
Reason: DNA-templated transcription is the synthesis of RNA from a DNA template. KDM4C is a chromatin-modifying coactivator whose role is regulatory, captured by the regulation of DNA-templated transcription row. Human KDM4C has no experimental annotation to this term and the KDM4 PANTHER node does not carry it.
results in demethylation of trimethyl H3K9 and in stimulation of androgen
GO:0006355 regulation of DNA-templated transcription
IEA GO_REF:0000104
ACCEPT
Summary: KDM4C demethylates H3K9me3 at androgen receptor target genes, stimulating their transcription.
Reason: Supported by human KDM4C data (PMID:17277772, coactivation of androgen receptor targets); the donkey enzyme conserves the catalytic domain. The direction of the effect is established only for the androgen receptor coactivator context in human cells, so the undirected regulation term is kept at the level the evidence for the equid protein allows rather than refined to positive regulation.
Summary: Broad but correct; KDM4C regulates gene expression through histone demethylation.
Reason: True (KDM4 PANTHER node), but entailed by the more specific regulation of DNA-templated transcription (GO:0006355) row accepted in this review.
Reason: Correct (human KDM4C, KDM4 subclass), but entailed by the more specific histone H3K9me2/H3K9me3 demethylase activity (GO:0140684) accepted in this review, which records that KDM4C acts on the higher methylation states.
subfamily members also functioned as trimethylation-specific demethylases
file:EQUAS/KDM4C/KDM4C-bioinformatics/RESULTS.md
All human 2-oxoglutarate-binding residues (Y134, N200, K208, K243), catalytic Fe-binding residues (H190, E192, H278) and Zn-binding residues (C236, H242, C308, C310) of the JmjC domain are conserved
Summary: The JmjC domain binds catalytic Fe(II) and a structural Zn(2+); all ligand residues are conserved.
Reason: Correct but generic. The specific metals are known for the KDM4C catalytic domain (Fe(II) at the HXE...H facial triad, Ni(2+) substituting in the crystal structure; a structural zinc site), and every ligand residue is conserved in the donkey protein. Replace with iron ion binding and zinc ion binding; both are cofactor-binding terms, non-core relative to the demethylase activity.
Summary: KDM4C also demethylates trimethylated H3K36, less efficiently than H3K9me3.
Reason: Correct, but KDM4C acts on the trimethyl state (to lower states), paralleling the H3K9me2/H3K9me3 term used for its K9 activity. KDM4A-C form the vertebrate-conserved dual-specificity subclass whose H3K36-binding residues are conserved; refine to histone H3K36me2/H3K36me3 demethylase activity.
Summary: KDM4C removes methyl groups from trimethylated H3K9 in an Fe(II)/2-oxoglutarate-dependent dioxygenase reaction (EC 1.14.11.66).
Reason: The most specific accurate description of the core catalytic activity (human KDM4C, same PANTHER subfamily SF104); the donkey protein conserves every active-site residue, including the H190/E192 iron ligands whose mutation inactivates human KDM4C.
All human 2-oxoglutarate-binding residues (Y134, N200, K208, K243), catalytic Fe-binding residues (H190, E192, H278) and Zn-binding residues (C236, H242, C308, C310) of the JmjC domain are conserved
Core Functions
Fe(II)/2-oxoglutarate-dependent histone demethylase that removes trimethyl marks from histone H3 lysine 9 on chromatin, derepressing transcription of target genes such as androgen receptor targets.
Q: Which genomic loci and transcription factors recruit KDM4C in equid tissues, and does KDM4C act on H3K9me3 in heterochromatin as well as at androgen receptor target genes?
Q: Do the KDM4C PHD and double Tudor domains bind the same methylated histone marks (H3K4me3, H4K20me3) as the KDM4A Tudor domain, and does this targeting determine where H3K9me3 is removed?
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of the single ProtNLM2 GO prediction for donkey KDM4C (A0A9L0K3L6), a JmjC-domain histone demethylase 91% identical to human KDM4C with a fully conserved Fe(II)/2-oxoglutarate active site. The prediction histone H3K9me2/H3K9me3 demethylase activity (GO:0140684) is correct and already present in donkey GOA (CNN). ProtNLM2 also emitted the function text "Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code", which agrees with the H3K9 activity of human KDM4C but omits its H3K36me3 demethylase activity; no subcellular location was emitted. Non-GO outputs are noted, not scored.
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: Human KDM4C (JMJD2C) is an experimentally characterized H3K9 tridemethylase, and JMJD2 subfamily members convert H3K9me3 to lower methylation states. The donkey protein is 91% identical to human KDM4C and conserves every 2-oxoglutarate-, Fe(II)- and Zn(2+)-binding residue of the JmjC domain, so the activity transfers with high confidence. The exact term is already in donkey GOA (EC 1.14.11.66 mapping), so the prediction is correct but not novel. Training-set membership is unknown.
Supporting Evidence:
PMID:17277772: "JMJD2C as the first histone tridemethylase regulating androgen receptor"
PMID:16603238: "subfamily members also functioned as trimethylation-specific demethylases"
file:EQUAS/KDM4C/KDM4C-bioinformatics/RESULTS.md: "All human 2-oxoglutarate-binding residues (Y134, N200, K208, K243), catalytic Fe-binding residues (H190, E192, H278) and Zn-binding residues (C236, H242, C308, C310) of the JmjC domain are conserved"