KDM8

Summary

KDM8 (lysine demethylase 8, HGNC:25840) is a protein-coding gene on chromosome 16p12.1, encoding Bifunctional peptidase and arginyl-hydroxylase JMJD5 (Q8N371). Bifunctional enzyme that acts both as an endopeptidase and 2-oxoglutarate-dependent monooxygenase. It is a selective cancer dependency (DepMap: 58.3% of cell lines).

This gene likely encodes a histone lysine demethylase. Studies of a similar protein in mouse indicate a potential role for this protein as a tumor suppressor. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 79831 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 100 total
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 58.3% of screened cell lines
• MANE Select transcript: NM_024773

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25840
Approved symbol	KDM8
Name	lysine demethylase 8
Location	16p12.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13798
Ensembl gene	ENSG00000155666
Ensembl biotype	protein_coding
OMIM	611917
Entrez	79831

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 4 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000286096, ENST00000441782, ENST00000562269, ENST00000562733, ENST00000563571, ENST00000563881, ENST00000564961, ENST00000567366, ENST00000567735, ENST00000567785, ENST00000568792, ENST00000568965, ENST00000569329, ENST00000569592, ENST00000869409, ENST00000869410, ENST00000869411, ENST00000869412, ENST00000869413, ENST00000869414, ENST00000869415, ENST00000869416, ENST00000869417, ENST00000869418, ENST00000922391, ENST00000922392, ENST00000922393

RefSeq mRNA: 2 — MANE Select: NM_024773 NM_001145348, NM_024773

CCDS: CCDS10627, CCDS45448

Canonical transcript exons

ENST00000286096 — 8 exons

Exon	Start	End
ENSE00001139326	27213585	27213751
ENSE00001181234	27220566	27221768
ENSE00001902285	27203526	27203636
ENSE00003473573	27210093	27210621
ENSE00003485831	27214876	27215008
ENSE00003548460	27215945	27215989
ENSE00003607991	27218961	27219110
ENSE00003613298	27220393	27220485

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 95.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.0455 / max 81.2498, expressed in 1653 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153298	2.5457	1292
153297	2.3674	1278
153299	0.0623	15
207817	0.0149	7
153304	0.0122	6
153301	0.0121	4
153302	0.0114	6
153303	0.0110	6
153300	0.0086	6

Top tissues by expression

271 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	95.83	gold quality
liver	UBERON:0002107	89.42	gold quality
duodenum	UBERON:0002114	82.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.59	gold quality
small intestine	UBERON:0002108	80.96	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.69	gold quality
granulocyte	CL:0000094	80.08	gold quality
apex of heart	UBERON:0002098	79.54	gold quality
colonic epithelium	UBERON:0000397	79.30	gold quality
body of pancreas	UBERON:0001150	78.76	gold quality
prefrontal cortex	UBERON:0000451	77.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	77.10	gold quality
mucosa of transverse colon	UBERON:0004991	76.79	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	76.46	gold quality
gall bladder	UBERON:0002110	76.45	gold quality
pituitary gland	UBERON:0000007	76.29	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.27	gold quality
adenohypophysis	UBERON:0002196	76.07	gold quality
ventricular zone	UBERON:0003053	75.99	gold quality
ganglionic eminence	UBERON:0004023	75.90	gold quality
jejunal mucosa	UBERON:0000399	75.87	gold quality
cerebellar hemisphere	UBERON:0002245	75.81	gold quality
cerebellar cortex	UBERON:0002129	75.78	gold quality
pancreas	UBERON:0001264	75.74	gold quality
right adrenal gland	UBERON:0001233	75.73	gold quality
tendon of biceps brachii	UBERON:0008188	75.68	silver quality
spleen	UBERON:0002106	75.63	gold quality
left adrenal gland	UBERON:0001234	75.61	gold quality
bone marrow cell	CL:0002092	75.55	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MBD2, NR1I2

miRNA regulators (miRDB)

42 targeting KDM8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-6876-3P	98.97	65.69	765
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-626	98.89	66.21	762
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-548S	98.50	67.17	1213
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-4275	97.96	68.42	1549
HSA-MIR-637	97.91	64.05	1517

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 58.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 26)

• Identifies five novel candidate tumor suppressor genes in mouse, including Pou2f2, Hivep3, Jmjd5, Fbxl10 and a protein similar to human N4BP3. (PMID:16858412)
• show that JMJD5 (now renamed KDM8), demethylates H3K36me2 and is required for cell cycle progression. (PMID:20457893)
• Data show that both Arabidopsis jmjd5 mutant seedlings and mammalian cell cultures deficient for the human ortholog of this gene have similar fast-running circadian oscillations compared with WT. (PMID:21115819)
• JMJD5 is a post-translational co-repressor for NFATc1 that attenuates osteoclastogenesis. (PMID:22375008)
• The study reports high-resolution crystal structures of the human JMJD5 catalytic domain in complex with the substrate 2-oxoglutarate (2-OG) and the inhibitor N-oxalylglycine (NOG). (PMID:22851697)
• These results reveal that the N-terminal domain is essential for the nuclear localization of JMJD5 and its normal enzymatic function towards substrates in the nucleus (PMID:23948433)
• Comparison of the structure of JMJD5 with that of FIH, a well characterized protein hydroxylase, reveals that human JMJD5 might function as a protein hydroxylase. (PMID:24100311)
• JMJD5 has a role in regulating PKM2 nuclear translocation and reprogramming HIF-1alpha-mediated glucose metabolism (PMID:24344305)
• we provide genetic and biochemical evidence that the JMJD5/CDKN1A (p21) axis is essential to maintaining the short G1 phase which is critical for pluripotency in human embryonic stem cells (PMID:24740926)
• RCCD1 and KDM8 form a histone demethylase complex. (PMID:24981860)
• results reveal that JMJD5 is a novel binding partner of p53 and it functions as a positive modulator of cell cycle and cell proliferation mainly through the repression of p53 pathway. (PMID:26025680)
• Suggest JMJD5 as a potential oncogene in colon carcinogenesis. (PMID:26261525)
• Data suggest that JMJD5 partially accumulates on mitotic spindles during mitosis; depletion of JMJD5 results in significant mitotic arrest, spindle assembly defects, and sustained activation of spindle assembly checkpoint. (PMID:26710852)
• JMJD5 is a tumor suppressor gene in HCC pathogenesis, and the epigenetic silencing of JMJD5 promotes HCC cell proliferation by directly down-regulating CDKN1A transcription. (PMID:26760772)
• These results suggest that direct interaction of JMJD5 with HBx facilitates hepatitis B virus replication through the hydroxylase activity of JMJD5. (PMID:26792738)
• JMJD5 depletion increases the susceptibility of cancer cells to microtubule-destabilizing agents. (PMID:27715397)
• The protease activities of JMJD5 and JMJD7 represent a mechanism for removal of histone tails bearing methylated arginine residues and define a potential mechanism of transcription regulation. (PMID:28847961)
• Here, we report that JMJD5, a Jumonji C (JmjC) domain-containing protein, is a Cathepsin L-type protease that mediates histone H3 N-tail proteolytic cleavage under stress conditions that cause a DNA damage response. (PMID:28982940)
• Recognition between JMJD5/JMJD7 and histone substrates is specific, which is reflected by the binding data between enzymes and substrates. High structural similarity between JMJD5 and JMJD7 is reflected by the shared common substrates and high binding affinity. (PMID:29459673)
• JMJD5 catalyzes stereoselective C-3 hydroxylation of arginine residues in sequences from human RCCD1 and ribosomal protein S6. (PMID:29563586)
• KDM8/JMJD5exhibits a novel property as a dual coactivator of AR and PKM2 and as such, it is a potent inducer of castration and therapy resistance.Its oncogenic properties in prostate cancer come from its direct interaction with AR to affect androgen response and with PKM2 to regulate tumor metabolism. (PMID:30072740)
• JMJD5 expression is increased in oral squamous cell carcinoma tissue samples and tumor cell lines. (PMID:30551455)
• Downregulation of Jumonji-C domain-containing protein 5 inhibits proliferation by silibinin in the oral cancer PDTX model. (PMID:32678829)
• JMJD5 couples with CDK9 to release the paused RNA polymerase II. (PMID:32747552)
• Jumonji-C domain-containing protein 5 suppresses proliferation and aerobic glycolysis in pancreatic cancer cells in a c-Myc-dependent manner. (PMID:35176452)
• JMJD5 inhibits lung cancer progression by facilitating EGFR proteasomal degradation. (PMID:37813845)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdm8	ENSDARG00000102512
mus_musculus	Kdm8	ENSMUSG00000030752
rattus_norvegicus	Kdm8	ENSRNOG00000015180
drosophila_melanogaster	JMJD5	FBGN0035166
caenorhabditis_elegans		WBGENE00007387

Paralogs (4): TYW5 (ENSG00000162971), HIF1AN (ENSG00000166135), HSPBAP1 (ENSG00000169087), JMJD7 (ENSG00000243789)

Protein

Protein identifiers

Bifunctional peptidase and arginyl-hydroxylase JMJD5 — Q8N371 (reviewed: Q8N371)

Alternative names: JmjC domain-containing protein 5, Jumonji C domain-containing protein 5, L-arginine (3R)-hydroxylase KDM8

All UniProt accessions (7): Q8N371, A0A0S2Z5P4, A0A0S2Z5P8, A0A0S2Z5T1, H3BM39, H3BPT5, H3BR76

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme that acts both as an endopeptidase and 2-oxoglutarate-dependent monooxygenase. Endopeptidase that cleaves histones N-terminal tails at the carboxyl side of methylated arginine or lysine residues, to generate ’tailless nucleosomes’, which may trigger transcription elongation. Preferentially recognizes and cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4. After initial cleavage, continues to digest histones tails via its aminopeptidase activity. Upon DNA damage, cleaves the N-terminal tail of histone H3 at monomethylated lysine residues, preferably at monomethylated ‘Lys-9’ (H3K9me1). The histone variant H3F3A is the major target for cleavage. Additionally, acts as a Fe(2+) and 2-oxoglutarate-dependent monooxygenase, catalyzing (R)-stereospecific hydroxylation at C-3 of ‘Arg-137’ of RPS6 and ‘Arg-141’ of RCCD1, but the biological significance of this activity remains to be established. Regulates mitosis through different mechanisms: Plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with RCCD1. Possibly together with RCCD1, is involved in proper mitotic spindle organization and chromosome segregation. Negatively regulates cell cycle repressor CDKN1A/p21, which controls G1/S phase transition. Required for G2/M phase cell cycle progression. Regulates expression of CCNA1/cyclin-A1, leading to cancer cell proliferation. Also, plays a role in regulating alpha-tubulin acetylation and cytoskeletal microtubule stability involved in epithelial to mesenchymal transition. Regulates the circadian gene expression in the liver. Represses the transcriptional activator activity of the CLOCK-BMAL1 heterodimer in a catalytically-independent manner. Negatively regulates the protein stability and function of CRY1; required for AMPK-FBXL3-induced CRY1 degradation.

Subunit / interactions. Can form homodimers (via JmjC domain). Found in a complex with RCCD1. Interacts (via N-terminus) with RCCD1 (via N-terminus); this interaction stimulates H3K36me3 and H3K36me2 demethylation. Interacts (via JmjC domain) with H3C1. Interacts with FBXL3 and PSMD2. Interacts with CRY1 in a FBXL3-dependent manner.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Weakly expressed in most cells. Highly expressed in breast cancer cells. Expressed in embryonic stem cells.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Induction. Up-regulated upon starvation, DNA replication stress, UV treatment and by camptothecin and etoposide treatment.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N371-1	1	yes
Q8N371-2	2
Q8N371-3	3

RefSeq proteins (2): NP_001138820, NP_079049* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003347	JmjC_dom	Domain
IPR041667	Cupin_8	Domain
IPR056520	ARM_KDM8_N	Domain

Pfam: PF13621, PF24472

Enzyme classification (BRENDA):

• EC 1.14.11.27 — [histone H3]-dimethyl-L-lysine36 demethylase (BRENDA: 7 organisms, 38 substrates, 0 inhibitors, 0 Km, 0 kcat entries)
• EC 1.14.11.73 — [protein]-arginine 3-hydroxylase (BRENDA: 2 organisms, 5 substrates, 1 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• L-arginyl-[protein] + 2-oxoglutarate + O2 = (3R)-3-hydroxy-L-arginyl-[protein] + succinate + CO2 (RHEA:56744)

UniProt features (67 total): strand 16, binding site 15, mutagenesis site 15, helix 11, turn 3, splice variant 2, chain 1, domain 1, region of interest 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
4GJZ	X-RAY DIFFRACTION	1.05
6F4Q	X-RAY DIFFRACTION	1.12
6F4T	X-RAY DIFFRACTION	1.22
4GJY	X-RAY DIFFRACTION	1.25
6F4O	X-RAY DIFFRACTION	1.28
6F4R	X-RAY DIFFRACTION	1.3
6I9N	X-RAY DIFFRACTION	1.36
6F4P	X-RAY DIFFRACTION	1.45
6F4S	X-RAY DIFFRACTION	1.46
7UQ3	X-RAY DIFFRACTION	1.49
6I9L	X-RAY DIFFRACTION	1.53
4QU1	X-RAY DIFFRACTION	1.57
7DYT	X-RAY DIFFRACTION	1.62
6I9M	X-RAY DIFFRACTION	1.65
6F4M	X-RAY DIFFRACTION	1.71
7DYU	X-RAY DIFFRACTION	1.72
7DYV	X-RAY DIFFRACTION	1.92
6AVS	X-RAY DIFFRACTION	2.02
7DYW	X-RAY DIFFRACTION	2.13
6AX3	X-RAY DIFFRACTION	2.25
7DYX	X-RAY DIFFRACTION	2.27
3UYJ	X-RAY DIFFRACTION	2.35
5FBJ	X-RAY DIFFRACTION	2.42
6F4N	X-RAY DIFFRACTION	2.54
4AAP	X-RAY DIFFRACTION	2.6
4GAZ	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N371-F1	89.40	0.76

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (15): 321; 321; 323; 327; 336; 400; 400; 414; 238; 272; 275; 275 …

Mutagenesis-validated functional residues (15):

Position	Phenotype
1–182	no effect on l-arginyl 3-hydroxylase activity toward rps6.
238	loss of l-arginyl 3-hydroxylase activity toward rps6.
243	loss of l-arginyl 3-hydroxylase activity toward rps6.
275	loss of l-arginyl 3-hydroxylase activity toward rps6. loss of peptidase activity toward methylated histones.
310	loss of l-arginyl 3-hydroxylase activity toward rps6.
321–323	fails to cleave h3c1.
321	loss of h3k36me2 demethylase activity.
321	loss of l-arginyl 3-hydroxylase activity toward rps6. loss of peptidase activity toward methylated histones; when associ
323	loss of peptidase activity toward methylated histones; when associated with a-321 and a-400.
335–336	loss of interaction with h3c1. fails to cleave h3c1.
336	loss of peptidase activity toward methylated histones.
356	reduces l-arginyl 3-hydroxylase activity toward rps6 substrate.
398–400	fails to cleave h3c1.
400	loss of peptidase activity toward methylated histones; when associated with a-321 and a-323.
414	reduces l-arginyl 3-hydroxylase activity toward rps6.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9629569	Protein hydroxylation
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 110 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, MARTINEZ_RB1_TARGETS_UP, GOBP_PROTEIN_DESTABILIZATION, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, INGRAM_SHH_TARGETS_DN, CAIRO_HEPATOBLASTOMA_DN, GOBP_REGULATION_OF_PROTEIN_STABILITY, GOBP_MITOTIC_CELL_CYCLE, GOBP_CELL_CYCLE_G2_M_PHASE_TRANSITION, GOBP_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, BALLIF_DEVELOPMENTAL_DISABILITY_P16_P12_DELETION

GO Biological Process (13): G2/M transition of mitotic cell cycle (GO:0000086), in utero embryonic development (GO:0001701), proteolysis (GO:0006508), protein destabilization (GO:0031648), circadian regulation of gene expression (GO:0032922), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), fibroblast proliferation (GO:0048144), regulation of signal transduction by p53 class mediator (GO:1901796), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), regulation of gene expression (GO:0010468), rhythmic process (GO:0048511)

GO Molecular Function (12): p53 binding (GO:0002039), chromatin binding (GO:0003682), endopeptidase activity (GO:0004175), aminopeptidase activity (GO:0004177), metal ion binding (GO:0046872), histone H3K36 demethylase activity (GO:0051864), peptidyl-arginine 3-dioxygenase activity (GO:0106157), protein binding (GO:0005515), peptidase activity (GO:0008233), oxidoreductase activity (GO:0016491), hydrolase activity (GO:0016787), dioxygenase activity (GO:0051213)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
regulation of DNA-templated transcription	2
binding	2
2-oxoglutarate-dependent dioxygenase activity	2
catalytic activity, acting on a protein	2
catalytic activity	2
cellular anatomical structure	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
chordate embryonic development	1
protein metabolic process	1
regulation of protein stability	1
circadian rhythm	1
regulation of gene expression	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cell population proliferation	1
signal transduction by p53 class mediator	1
regulation of intracellular signal transduction	1
cellular component organization	1
chromatin organization	1
gene expression	1
regulation of macromolecule biosynthetic process	1
biological_process	1
protein binding	1
peptidase activity	1
exopeptidase activity	1
cation binding	1
histone H3 demethylase activity	1
hydrolase activity	1
oxidoreductase activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1

Protein interactions and networks

STRING

702 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDM8	PKM	P14618	826
KDM8	BLM	P54132	719
KDM8	JMJD6	Q6NYC1	690
KDM8	RCCD1	A6NED2	668
KDM8	KDM4A	O75164	661
KDM8	RIOX1	Q9H6W3	648
KDM8	RIOX2	Q8IUF8	594
KDM8	KDM5A	P29375	566
KDM8	KDM7A	Q6ZMT4	564
KDM8	KDM4C	Q9H3R0	563
KDM8	KDM3A	Q9Y4C1	556
KDM8	KDM3B	Q7LBC6	552
KDM8	KDM4B	O94953	539
KDM8	KDM2A	Q9Y2K7	538
KDM8	KDM6B	O15054	533

IntAct

24 interactions, top by confidence:

A	B	Type	Score
ISY1	AQR	psi-mi:“MI:0914”(association)	0.740
KDM8	RCCD1	psi-mi:“MI:0915”(physical association)	0.710
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
YJU2B	RCCD1	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
ECE1	KDM8	psi-mi:“MI:0915”(physical association)	0.370
PCYT2	KDM8	psi-mi:“MI:0915”(physical association)	0.370
KDM8	HMGN1	psi-mi:“MI:0914”(association)	0.350
EFNA4	NBAS	psi-mi:“MI:0914”(association)	0.350
CSTL1	DENND11	psi-mi:“MI:0914”(association)	0.350
COX4I2	COX7A2L	psi-mi:“MI:0914”(association)	0.350
TPST2	NDC80	psi-mi:“MI:0914”(association)	0.350
GLCE	TNPO2	psi-mi:“MI:0914”(association)	0.350
MFNG	PLSCR1	psi-mi:“MI:0914”(association)	0.350
FCER1A	STX6	psi-mi:“MI:0914”(association)	0.350
UNC5CL	INSR	psi-mi:“MI:0914”(association)	0.350
RCCD1	IFT56	psi-mi:“MI:0914”(association)	0.350
ISY1	RCCD1	psi-mi:“MI:0914”(association)	0.350
CAPN8	CAST	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): KDM8 (Affinity Capture-MS), KDM8 (Two-hybrid), KDM8 (Affinity Capture-MS), KDM8 (Affinity Capture-MS), KDM8 (Affinity Capture-MS), KDM8 (Affinity Capture-MS), PKM (Affinity Capture-MS), PKM (Affinity Capture-Western), KDM8 (Affinity Capture-Western), PKM (Reconstituted Complex), PKM (Co-localization), KDM8 (Co-localization), MEOX2 (Two-hybrid), KDM8 (Affinity Capture-MS), KDM8 (Synthetic Lethality)

ESM2 similar proteins: A2AA28, A2RRH5, A4FV42, A6NDL7, A7MCT6, B0K012, B2RYG8, D3YWP0, D3ZRW8, E1B8U2, J3S6Y1, P21964, P50747, Q0V8R7, Q1JP61, Q2TBI8, Q3SZD4, Q3U2J5, Q4VBE8, Q58DC7, Q5E9Y6, Q5RJL2, Q5VZV1, Q6DJF8, Q6GQ33, Q6P9U1, Q7Z624, Q80WC9, Q86XA0, Q8BNV1, Q8C436, Q8CDZ2, Q8IZ69, Q8N371, Q8R1C6, Q8WU66, Q920N2, Q96AZ1, Q96CB9, Q96RR1

Diamond homologs: A2RUC4, A8E534, B2GUS6, B5XF11, E1C7T6, Q1JP61, Q497B8, Q54LV7, Q55DF5, Q5BKC6, Q6AXL5, Q8N371, Q8RWR1, Q9CXT6, Q9NWT6, Q9W0M3, Q54FG7, Q6C3P4, Q08BV2, A2RSX7, Q2U6D4, Q3TA59, Q4IER0, Q5BH52, Q9P3K9, P59723, Q0WVR4, Q58CU3, Q5UQY3, Q8BK58, Q8BLR9, Q96EW2, F4K2M8, Q54FM1, Q6AY40

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

100 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1543 predictions. Top by Δscore:

Variant	Effect	Δscore
16:27210091:A:AG	acceptor_gain	1.0000
16:27210092:G:GG	acceptor_gain	1.0000
16:27210092:GGCAC:G	acceptor_gain	1.0000
16:27210618:AAAGG:A	donor_loss	1.0000
16:27210620:AGGTA:A	donor_loss	1.0000
16:27210621:GGTA:G	donor_loss	1.0000
16:27210622:G:T	donor_loss	1.0000
16:27210623:T:A	donor_loss	1.0000
16:27215006:GAGGT:G	donor_loss	1.0000
16:27215007:AGGT:A	donor_loss	1.0000
16:27215009:G:GC	donor_loss	1.0000
16:27215010:T:A	donor_loss	1.0000
16:27215924:T:A	acceptor_gain	1.0000
16:27215925:G:A	acceptor_gain	1.0000
16:27215934:C:CA	acceptor_gain	1.0000
16:27220560:CTTCA:C	acceptor_loss	1.0000
16:27220561:TTCA:T	acceptor_loss	1.0000
16:27220562:TCA:T	acceptor_loss	1.0000
16:27220563:CA:C	acceptor_loss	1.0000
16:27220564:A:AG	acceptor_gain	1.0000
16:27220565:G:A	acceptor_loss	1.0000
16:27220565:G:GG	acceptor_gain	1.0000
16:27225724:A:AC	donor_gain	1.0000
16:27225725:C:CC	donor_gain	1.0000
16:27203632:GAGAG:G	donor_gain	0.9900
16:27203634:GAG:G	donor_gain	0.9900
16:27203636:GGTT:G	donor_loss	0.9900
16:27203637:G:T	donor_loss	0.9900
16:27203638:T:A	donor_loss	0.9900
16:27204120:G:T	donor_gain	0.9900

AlphaMissense

2729 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:27214914:T:A	V235D	0.999
16:27219045:T:A	W310R	0.997
16:27219045:T:C	W310R	0.997
16:27219078:C:G	H321D	0.997
16:27213747:T:A	W221R	0.996
16:27213747:T:C	W221R	0.996
16:27220713:A:C	S412R	0.996
16:27220715:C:A	S412R	0.996
16:27220715:C:G	S412R	0.996
16:27220701:A:C	S408R	0.995
16:27220703:C:A	S408R	0.995
16:27220703:C:G	S408R	0.995
16:27215967:C:A	A274D	0.994
16:27219052:G:A	G312D	0.994
16:27220480:A:C	S361R	0.994
16:27220482:C:A	S361R	0.994
16:27220482:C:G	S361R	0.994
16:27214924:A:C	E238D	0.993
16:27214924:A:T	E238D	0.993
16:27214952:T:A	W248R	0.993
16:27214952:T:C	W248R	0.993
16:27218971:T:C	L285S	0.993
16:27215964:T:C	L273P	0.992
16:27220677:C:G	H400D	0.992
16:27213729:T:A	W215R	0.991
16:27213729:T:C	W215R	0.991
16:27214908:G:C	R233P	0.991
16:27214920:T:A	V237E	0.991
16:27213749:G:C	W221C	0.989
16:27213749:G:T	W221C	0.989

dbSNP variants (sampled 300 via entrez): RS1000047656 (16:27205426 A>T), RS1000129015 (16:27206737 T>A), RS1000315616 (16:27216787 C>T), RS1000379513 (16:27217854 A>C,G,T), RS1000435873 (16:27201747 G>C), RS1000934023 (16:27205815 G>A), RS1001039864 (16:27221626 G>C,T), RS1001187357 (16:27217449 A>C), RS1001221620 (16:27217713 G>A), RS1001293900 (16:27217044 G>A), RS1001368266 (16:27206064 C>A), RS1002375373 (16:27212244 A>G), RS1002473799 (16:27203920 TA>T), RS1002816314 (16:27212459 C>T), RS1002941809 (16:27203278 T>C,G)

Disease associations

OMIM: gene MIM:611917 | disease phenotypes: MIM:135900

GenCC curated gene-disease

Mondo (1): Coffin-Siris syndrome (MONDO:0015452)

Orphanet (1): Coffin-Siris syndrome (Orphanet:1465)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001762_796	Obesity-related traits	9.000000e-06
GCST003542_67	Night sleep phenotypes	4.000000e-06
GCST003875_18	Gut microbiota (bacterial taxa)	2.000000e-09
GCST008916_121	Asthma	2.000000e-17
GCST009391_1813	Metabolite levels	5.000000e-07
GCST009391_2083	Metabolite levels	4.000000e-07
GCST009391_832	Metabolite levels	2.000000e-06
GCST009391_929	Metabolite levels	9.000000e-07
GCST009391_943	Metabolite levels	7.000000e-06
GCST009391_945	Metabolite levels	3.000000e-07
GCST009798_67	Asthma	5.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007827	nighttime rest measurement
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement
EFO:0010404	triacylglycerol 48:1 measurement
EFO:0010373	phosphatidylcholine 32:1 measurement
EFO:0010399	triacylglycerol 44:1 measurement
EFO:0010401	triacylglycerol 46:1 measurement
EFO:0010402	triacylglycerol 46:2 measurement
EFO:0010403	triacylglycerol 48:0 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536436	Coffin-Siris syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523396 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,267 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2338329	ROXADUSTAT	4	1,063
CHEMBL3544988	DAPRODUSTAT	4	308
CHEMBL3646221	VADADUSTAT	4	533
CHEMBL4297619	ENARODUSTAT	3	109
CHEMBL4650314	DESIDUSTAT	3	254

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 1.14.11.- Histone demethylases

ChEMBL bioactivities

18 potent at pChembl≥5 of 30 total, top 18 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	IC50	300	nM	CHEMBL5419332
6.40	IC50	400	nM	CHEMBL5425339
6.40	IC50	400	nM	CHEMBL5408048
6.40	IC50	400	nM	CHEMBL5396670
6.30	IC50	500	nM	CHEMBL5407378
6.30	IC50	500	nM	CHEMBL316034
6.16	IC50	700	nM	CHEMBL5423565
6.16	IC50	700	nM	CHEMBL5428941
6.16	IC50	700	nM	CHEMBL5408058
6.05	IC50	900	nM	CHEMBL5402035
5.51	IC50	3100	nM	CHEMBL5429223
5.39	IC50	4100	nM	VADADUSTAT
5.35	IC50	4500	nM	CHEMBL5422782
5.24	IC50	5800	nM	CHEMBL5415306
5.16	IC50	7000	nM	CHEMBL6173707
5.12	IC50	7500	nM	CHEMBL5429166
5.07	IC50	8500	nM	DAPRODUSTAT
5.02	IC50	9500	nM	CHEMBL5414235

PubChem BioAssay actives

15 with measured affinity, of 27 total; 15 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-(4-phenylbutylamino)pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.3000	uM
5-[(4-methoxyphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.4000	uM
5-(benzylamino)pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.4000	uM
5-(1-phenylethylamino)pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.4000	uM
pyridine-2,4-dicarboxylic acid	2010689: Inhibition of N-terminal his6-tagged human recombinant JMJD5 (183 to 416 residues) using RPS6 as substrate by SPE-MS analysis	ic50	0.5000	uM
5-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.5000	uM
5-[(2-methoxyphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.7000	uM
5-[(2-cyclopropylphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.7000	uM
5-(cyclohexylmethylamino)pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.7000	uM
5-(3-phenylpropylamino)pyridine-2,4-dicarboxylic acid	2010688: Inhibition of N-terminal his6-tagged-thioredoxin-tagged human recombinant JMJD5 expressed in Escherichia coli using RPS6 as substrate by SPE-MS analysis	ic50	0.9000	uM
3-(1-phenylethylamino)pyridine-2,4-dicarboxylic acid	2010689: Inhibition of N-terminal his6-tagged human recombinant JMJD5 (183 to 416 residues) using RPS6 as substrate by SPE-MS analysis	ic50	3.1000	uM
5-fluoropyridine-2,4-dicarboxylic acid	2010689: Inhibition of N-terminal his6-tagged human recombinant JMJD5 (183 to 416 residues) using RPS6 as substrate by SPE-MS analysis	ic50	4.5000	uM
3-[(4-methoxyphenyl)methylamino]pyridine-2,4-dicarboxylic acid	2010689: Inhibition of N-terminal his6-tagged human recombinant JMJD5 (183 to 416 residues) using RPS6 as substrate by SPE-MS analysis	ic50	5.8000	uM
3-(1-phenylpropylamino)pyridine-2,4-dicarboxylic acid	2010689: Inhibition of N-terminal his6-tagged human recombinant JMJD5 (183 to 416 residues) using RPS6 as substrate by SPE-MS analysis	ic50	7.5000	uM
3-(benzylamino)pyridine-2,4-dicarboxylic acid	2010689: Inhibition of N-terminal his6-tagged human recombinant JMJD5 (183 to 416 residues) using RPS6 as substrate by SPE-MS analysis	ic50	9.5000	uM

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases expression	2
GSK-J4	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Doxorubicin	affects localization, affects binding, decreases reaction, affects reaction, increases expression	1
Methylnitronitrosoguanidine	affects binding, decreases reaction	1
N-Nitrosopyrrolidine	decreases expression	1
Ozone	affects expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4379088	Binding	Binding affinity to JMJD5 (unknown origin) at protein to compound concentration ratio of 1:10 by differential scanning fluorimetry	Discovery of 4H-Chromen-4-one Derivatives as a New Class of Selective Rho Kinase (ROCK) Inhibitors, which Showed Potent Activity in ex Vivo Diabetic Retinopathy Models. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.