JMJD6

Summary

JMJD6 (jumonji domain containing 6, arginine demethylase and lysine hydroxylase, HGNC:19355) is a protein-coding gene on chromosome 17q25.1, encoding Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (Q6NYC1). Dioxygenase that can both act as a arginine demethylase and a lysyl-hydroxylase. It is a selective cancer dependency (DepMap: 39.1% of cell lines).

This gene encodes a nuclear protein with a JmjC domain. JmjC domain-containing proteins are predicted to function as protein hydroxylases or histone demethylases. This protein was first identified as a putative phosphatidylserine receptor involved in phagocytosis of apoptotic cells; however, subsequent studies have indicated that it does not directly function in the clearance of apoptotic cells, and questioned whether it is a true phosphatidylserine receptor. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23210 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 58 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 39.1% of screened cell lines
• MANE Select transcript: NM_015167

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19355
Approved symbol	JMJD6
Name	jumonji domain containing 6, arginine demethylase and lysine hydroxylase
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	PTDSR1, KIAA0585
Ensembl gene	ENSG00000070495
Ensembl biotype	protein_coding
OMIM	604914
Entrez	23210

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000303996, ENST00000397625, ENST00000445478, ENST00000542934, ENST00000585429, ENST00000589982, ENST00000591460, ENST00000905303, ENST00000905304, ENST00000932856

RefSeq mRNA: 2 — MANE Select: NM_015167 NM_001081461, NM_015167

CCDS: CCDS42383, CCDS42384

Canonical transcript exons

ENST00000397625 — 6 exons

Exon	Start	End
ENSE00000745269	76725467	76725855
ENSE00000890541	76721798	76721933
ENSE00000890542	76723772	76724058
ENSE00002311720	76726347	76726606
ENSE00003462166	76718451	76718860
ENSE00003478839	76720360	76720498

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.5682 / max 1123.8292, expressed in 1819 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168276	13.0388	1808
168278	5.1829	1618
168277	4.8622	1606
168280	1.1517	583
168279	0.3515	122
168273	0.3268	115
168274	0.2589	103
168272	0.2462	88
168275	0.1491	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	97.12	gold quality
vena cava	UBERON:0004087	96.37	gold quality
cervix squamous epithelium	UBERON:0006922	95.09	gold quality
mucosa of stomach	UBERON:0001199	94.59	gold quality
lower esophagus mucosa	UBERON:0035834	94.45	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.18	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.16	gold quality
trachea	UBERON:0003126	93.95	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.94	gold quality
pericardium	UBERON:0002407	93.92	gold quality
lower esophagus	UBERON:0013473	93.92	gold quality
popliteal artery	UBERON:0002250	93.87	gold quality
tibial artery	UBERON:0007610	93.85	gold quality
right atrium auricular region	UBERON:0006631	93.76	gold quality
adenohypophysis	UBERON:0002196	93.67	gold quality
pylorus	UBERON:0001166	93.42	gold quality
aorta	UBERON:0000947	93.41	gold quality
mucosa of transverse colon	UBERON:0004991	93.33	gold quality
granulocyte	CL:0000094	93.17	gold quality
omental fat pad	UBERON:0010414	93.05	gold quality
peritoneum	UBERON:0002358	93.04	gold quality
ascending aorta	UBERON:0001496	93.03	gold quality
cardiac atrium	UBERON:0002081	92.81	gold quality
thoracic aorta	UBERON:0001515	92.79	gold quality
pituitary gland	UBERON:0000007	92.64	gold quality
right lobe of liver	UBERON:0001114	92.58	gold quality
sigmoid colon	UBERON:0001159	92.58	gold quality
heart left ventricle	UBERON:0002084	92.57	gold quality
parotid gland	UBERON:0001831	92.52	gold quality
cardiac ventricle	UBERON:0002082	92.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
BRD4	Activation
CCND1	Activation
DCPS	Activation
DMAP1
HS1BP3
KAT5
MLF2
PIM2	Activation

miRNA regulators (miRDB)

10 targeting JMJD6, 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-5692A	100.00	74.40	6850
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-4288	97.11	67.23	1636

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 39.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. (PMID:11877474)
• plays a major role in the clearance of apoptotic cells from the thymus. (PMID:15072554)
• The mouse ortholog of Ptdsr is essential for the development and differentiation of multiple organs during embryogenesis but not for apoptotic cell clearance. (PMID:15345036)
• Homomultimer of PS-R might be playing an important function as a scaffolding protein in the nucleus. (PMID:17534701)
• study demonstrates that JMJD6 is a JmjC-containing iron- and 2-oxoglutarate-dependent dioxygenase that demethylates histone H3 at arginine 2 (H3R2) and histone H4 at arginine 3 (H4R3) in both biochemical and cell-based assays (PMID:17947579)
• Jmjd6 is predicted to have a conserved enzymatic function as a classical non-heme, Fe(II)- and 2OG-dependent dioxygenase, and is closely related to the JmjC domain-containing proteins Jmjd4 and JFP6. (PMID:18564434)
• Jmjd6 serves as a membrane-associated receptor that regulates phagocytosis in immature macrophages but is dispensable for phagocytosis. (PMID:19492415)
• study reveals the splicing factor U2AF65 undergoes posttranslational lysyl-5-hydroxylation catalyzed by Jmjd6; Jmjd6 is shown to change alternative RNA splicing of some endogenous & reporter genes, supporting a role for Jmjd6 in regulation of RNA splicing (PMID:19574390)
• Data show that JMJD6 bound efficiently to single-stranded RNA, but not to single-stranded DNA, double-stranded RNA, or double-stranded DNA. (PMID:20679243)
• crystallographic studies on the catalytic domain of JMJD6 in complex with Ni(II) substituting for Fe(II) (PMID:20684070)
• Jmjd6 regulates the splicing of Flt1, thereby controlling angiogenic sprouting. (PMID:21300889)
• we did not detect arginine demethylase activity for Jmjd6, but we did confirm that it could catalyze the lysyl-hydroxylation of histone peptides (PMID:22189873)
• data indicate JMJD6 has conserved functions and often affects similar pathways across multiple cell types; it has ability to promote cancer cell proliferation and motility; JMJD6 is a novel biomarker of tumor aggressiveness with functional implications in breast cancer growth and migration (PMID:22621393)
• Endothelial microparticles are incorporated by endothelial cells in an annexin I/phosphatidylserine receptor-dependent manner and protect target cells against apoptosis. (PMID:22701020)
• histones are additional substrates of JMJD6 in vivo. Because 5-hydroxylation of lysyl residues inhibited N-acetylation and N-methylation by an acetyltransferase and a methyltransferase (PMID:23303181)
• results showed that JMJD6 plays a key role in lung adenocarcinoma and therefore may provide an opportunity for developing a novel therapeutic target as well as a prognostic marker in lung adenocarcinoma. (PMID:23595221)
• The structure of Jmjd6 oligomers in vitro changes in the absence of the polyS domain, possibly reflecting the role of the polyS domain in nuclear/nucleolar shuttling of Jmjd6. (PMID:23688307)
• Study reports that a unique cohort of JMJD6 and Brd4 cobound distal enhancers, termed anti-pause enhancers, regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. (PMID:24360279)
• JMJD6 is a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention. (PMID:24667498)
• The expression of JMJD6 was reduced in T lymphocytes in chronic hepatitis B. (PMID:25219359)
• Although JMJD6 displays anti-tumoral properties in cell lines, its expression in breast tumours may be a marker of poor prognosis, suggesting that its function could be altered in breast cancer (PMID:25951181)
• A novel role for JMJD6 as an oxygen sensor in the human placenta, and alterations in the JMJD6-VHL-HIF1A feedback loop may indirectly contribute to elevated HIF1A found in preeclampsia. (PMID:26037477)
• Our studies identify JMJD6 as a molecular determinant of cancer stem cell phenotype (PMID:26645717)
• These findings provide evidence that JMJD6 may play a role in regulating the production of sFLT-1 in the preeclamptic placenta. Decreased placental JMJD6 expression may be an important component to the pathophysiology of preeclampsia. (PMID:26819475)
• Study identified a novel epigenetic mechanism showing how JMJD6 cooperates with Myc during oncogenic transformation. Combined high expression of Myc and JMJD6 confers a more aggressive phenotype in mouse and human tumors. (PMID:27081402)
• AcK27-HOXB9 suppresses the transcription of its target gene Jumonji domain-containing protein 6 (JMJD6) by direct occupying the promoter of JMJD6 gene. (PMID:27613418)
• JMJD6 regulated a large set of alternative splicing events, and importantly, its regulated splicing events were significantly overlapped those controlled by U2AF65. (PMID:27899633)
• knockdown of JMJD6 reduces the proliferation, migration and invasion of neuroglioma stem cells (PMID:28592121)
• High JMJD6 expression is associated with Neuroblastomas. (PMID:28684529)
• miR-770 acted on a tumor suppressor by binding to the 3’UTR of JMJD6 and downregulated its expression in NSCLC cells; this study also demonstrated that JMJD6 played as an oncogene in NSCLC cells (PMID:28882645)
• JMJD6 is a novel Stress Granule component that interacts with G3BP1 complexes, and its expression reduces G3BP1 monomethylation and asymmetric dimethylation at three Arg residues. (PMID:28972166)
• Results show that JMJD6 is up-regulated in melanoma, and high expression of JMJD6 protein is strongly correlated with advanced stages and aggressiveness of melanoma. It enhances the MAPK signaling through regulation of alternative splicing of PAK1 promoting multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. (PMID:29187213)
• In tumor samples but not normal breast tissue, the expression of JMJD6 linearly correlated with HOTAIR suggesting that JMJD6-mediated up-regulation may occur specifically in tumors. (PMID:29229759)
• JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. (PMID:29373688)
• Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERalpha-induced breast cancer cell growth and tumorigenesis, via modulation of recruitment of CARM1/MED12 co-activator complex. (PMID:29628309)
• results indicate for the first time that JMJD6 plays an important role in the regulation of ADSCs proliferation and migration through the modulation of PDE1C expression. (PMID:30092848)
• Inhibiting CDK4 abolished the ability of JMJD6 in enhancing cell proliferation. (PMID:30125344)
• The JMJD6-H2A.X(Y39ph) axis promoted triple negative breast cance cell growth via the autophagy pathway. (PMID:30185813)
• Biophysical analyses, including crystallographic analyses of JMJD6(Delta344-403) in complex with iron and 2OG, supported its assignment as a lysyl hydroxylase rather than an N-methyl arginyl-demethylase. The screening results supported some, but not all, of the assigned JMJD6 substrates and identified other potential JMJD6 substrates (PMID:31147442)
• JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. (PMID:31346162)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	jmjd6	ENSDARG00000102896
mus_musculus	Jmjd6	ENSMUSG00000056962
rattus_norvegicus	Jmjd6	ENSRNOG00000000250
drosophila_melanogaster	JMJD6	FBGN0038948
caenorhabditis_elegans		WBGENE00004205

Paralogs (2): JMJD4 (ENSG00000081692), JMJD8 (ENSG00000161999)

Protein

Protein identifiers

Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 — Q6NYC1 (reviewed: Q6NYC1)

Alternative names: Histone arginine demethylase JMJD6, JmjC domain-containing protein 6, Jumonji domain-containing protein 6, Lysyl-hydroxylase JMJD6, Peptide-lysine 5-dioxygenase JMJD6, Phosphatidylserine receptor

All UniProt accessions (4): Q6NYC1, B2WTI3, B2WTI4, K7EJU9

UniProt curated annotations — full annotation on UniProt →

Function. Dioxygenase that can both act as a arginine demethylase and a lysyl-hydroxylase. Acts as a lysyl-hydroxylase that catalyzes 5-hydroxylation on specific lysine residues of target proteins such as U2AF2/U2AF65 and LUC7L2. Regulates RNA splicing by mediating 5-hydroxylation of U2AF2/U2AF65, affecting the pre-mRNA splicing activity of U2AF2/U2AF65. Hydroxylates its own N-terminus, which is required for homooligomerization. Plays a role in the regulation of nucleolar liquid-liquid phase separation (LLPS) by post-translationally modifying LIAT1 at its lysine-rich domain which inhibits LIAT1 nucleolar targeting. In addition to peptidyl-lysine 5-dioxygenase activity, may act as an RNA hydroxylase, as suggested by its ability to bind single strand RNA. Also acts as an arginine demethylase which preferentially demethylates asymmetric dimethylation. Demethylates histone H3 at ‘Arg-2’ (H3R2me) and histone H4 at ‘Arg-3’ (H4R3me), including mono-, symmetric di- and asymmetric dimethylated forms, thereby playing a role in histone code. However, histone arginine demethylation may not constitute the primary activity in vivo. In collaboration with BRD4, interacts with the positive transcription elongation factor b (P-TEFb) complex in its active form to regulate polymerase II promoter-proximal pause release for transcriptional activation of a large cohort of genes. On distal enhancers, so called anti-pause enhancers, demethylates both histone H4R3me2 and the methyl cap of 7SKsnRNA leading to the dismissal of the 7SKsnRNA:HEXIM1 inhibitor complex. After removal of repressive marks, the complex BRD4:JMJD6 attract and retain the P-TEFb complex on chromatin, leading to its activation, promoter-proximal polymerase II pause release, and transcriptional activation. Demethylates other arginine methylated-proteins such as ESR1. Has no histone lysine demethylase activity. Required for differentiation of multiple organs during embryogenesis. Acts as a key regulator of hematopoietic differentiation: required for angiogenic sprouting by regulating the pre-mRNA splicing activity of U2AF2/U2AF65. Seems to be necessary for the regulation of macrophage cytokine responses.

Subunit / interactions. Homooligomerizes; requires lysyl-hydroxylase activity. Interacts with LUC7L2, LUC7L3 and U2AF2/U2AF65. Interacts with CDK9 and CCNT1; the interaction is direct with CDK9 and associates the P-TEFb complex when active. Interacts (via JmjC and N-terminal domains) with BRD4 (via NET domain); the interaction is stronger in presence of ssRNA and recruits JMJD6 on distal enhancers. Interacts with ARGLU1; interaction may be involved in ARGLU1-mediated modulation of alternative splicing.

Subcellular location. Nucleus. Nucleoplasm. Nucleolus. Cytoplasm.

Tissue specificity. Highly expressed in the heart, skeletal muscle and kidney. Expressed at moderate or low level in brain, placenta, lung, liver, pancreas, spleen, thymus, prostate, testis and ovary. Up-regulated in many patients with chronic pancreatitis. Expressed in nursing thymic epithelial cells.

Post-translational modifications. Hydroxylates its own N-terminus; hydroxylation is required for homooligomerization.

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

Domain organisation. The nuclear localization signal motifs are necessary and sufficient to target it into the nucleus.

Induction. Up-regulated upon cytokine treatment, but not upon TNF treatment.

Similarity. Belongs to the JMJD6 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6NYC1-1	1, Alpha	yes
Q6NYC1-2	2, Beta
Q6NYC1-3	3

RefSeq proteins (2): NP_001074930, NP_055982* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003347	JmjC_dom	Domain
IPR050910	JMJD6_ArgDemeth/LysHydrox	Family

Pfam: PF02373

Enzyme classification (BRENDA):

• EC 1.14.11.4 — procollagen-lysine 5-dioxygenase (BRENDA: 11 organisms, 68 substrates, 38 inhibitors, 43 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.011–0.25	8
(ILE-LYS-GLY)3	0.31–0.8	6
ASCORBATE	0.05–0.35	5
(IKG)3	0.4–5	3
ALA-ARG-GLY-ILE-LYS-GLY-ILE-ARG-GLY-PHE-SER-GLY	0.4–0.6	3
TYPE I PROCOLLAGEN	0.08–0.23	3
TYPE IV PROCOLLAGEN	0.04–0.3	3
(L-ILE-L-LYS-GLY)3	0.43	1
(PRO-PRO-GLY)4-ALA-ARG-GLY-MET-LYS-GLY-HIS-ARG-G	0.2	1
ALA-ARG-GLY-MET-LYS-GLY-HIS-ARG-GLY-(PRO-PRO-GLY	0.2	1
PEPTIDE (IKG)3	0.169	1
PROCOLLAGEN L-LYSINE	0.1	1

Catalyzed reactions (Rhea), 4 shown:

• N(omega),N(omega)’-dimethyl-L-arginyl-[protein] + 2 2-oxoglutarate + 2 O2 = L-arginyl-[protein] + 2 formaldehyde + 2 succinate + 2 CO2 (RHEA:58348)
• L-lysyl-[protein] + 2-oxoglutarate + O2 = (5S)-5-hydroxy-L-lysyl-[protein] + succinate + CO2 (RHEA:58360)
• N(omega),N(omega)’-dimethyl-L-arginyl-[protein] + 2-oxoglutarate + O2 = N(omega)-methyl-L-arginyl-[protein] + formaldehyde + succinate + CO2 (RHEA:58472)
• a 5’-end methyltriphosphate-guanosine-ribonucleotide-snRNA + 2-oxoglutarate + O2 = a 5’-end triphospho-guanosine-ribonucleotide-snRNA + formaldehyde + succinate + CO2 + H(+) (RHEA:58784)

UniProt features (74 total): helix 23, strand 13, mutagenesis site 12, binding site 7, short sequence motif 5, turn 5, splice variant 2, compositionally biased region 2, chain 1, domain 1, modified residue 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3K2O	X-RAY DIFFRACTION	1.75
6GDY	X-RAY DIFFRACTION	2.04
6MEV	X-RAY DIFFRACTION	2.6
3LD8	X-RAY DIFFRACTION	2.7
3LDB	X-RAY DIFFRACTION	2.7
6BNH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NYC1-F1	88.56	0.84

Antibody-complex structures (SAbDab): 2 — 3LD8, 3LDB

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 (7): 184; 187; 189; 197; 204; 273; 285

Post-translational modifications (1): 38

Mutagenesis-validated functional residues (12):

Position	Phenotype
85	decreases interaction with the net domain of brd4.
90	nearly abolishes the interaction with the net domain of brd4.
91	nearly abolishes the interaction with the net domain of brd4.
95	nearly abolishes the interaction with the net domain of brd4.
131	abolishes 2-oxoglutarate-binding and enzyme activity.
187	loss of histone arginine demethylase and lysyl-hydroxylase activities. abolishes homooligomerisation. loss of arginine d
189	loss of arginine demethylase and a lysyl-hydroxylase activities; when associated with a-187 and a-273.
204	impairs enzyme activity without affecting 2-oxoglutarate-binding.
231	impairs both hydroxylation activity and 2-oxoglutarate turnover assays.
273	loss of arginine demethylase and a lysyl-hydroxylase activities; when associated with a-187 and a-189.
285	impairs enzyme activity and 2-oxoglutarate-binding.
287	impairs enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-3214842	HDMs demethylate histones
R-HSA-9629569	Protein hydroxylation
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-392499	Metabolism of proteins
R-HSA-4839726	Chromatin organization
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 257 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_ERYTHROCYTE_HOMEOSTASIS, MENSE_HYPOXIA_UP, GOBP_OXIDATIVE_DEMETHYLATION, GOBP_APOPTOTIC_CELL_CLEARANCE, GOBP_VESICLE_MEDIATED_TRANSPORT, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_DEMETHYLATION

GO Biological Process (26): kidney development (GO:0001822), sprouting angiogenesis (GO:0002040), chromatin remodeling (GO:0006338), mRNA processing (GO:0006397), phagocytosis (GO:0006909), cell surface receptor signaling pathway (GO:0007166), heart development (GO:0007507), RNA splicing (GO:0008380), peptidyl-lysine hydroxylation to 5-hydroxy-L-lysine (GO:0018395), lung development (GO:0030324), negative regulation of protein homooligomerization (GO:0032463), T cell differentiation in thymus (GO:0033077), oxidative RNA demethylation (GO:0035513), macrophage activation (GO:0042116), recognition of apoptotic cell (GO:0043654), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of mRNA splicing, via spliceosome (GO:0048024), erythrocyte development (GO:0048821), protein homooligomerization (GO:0051260), retina development in camera-type eye (GO:0060041), membraneless organelle assembly (GO:0140694), blood vessel development (GO:0001568), chromatin organization (GO:0006325), cell differentiation (GO:0030154), apoptotic cell clearance (GO:0043277)

GO Molecular Function (17): RNA binding (GO:0003723), single-stranded RNA binding (GO:0003727), iron ion binding (GO:0005506), histone demethylase activity (GO:0032452), histone H3R2 demethylase activity (GO:0033746), histone H4R3 demethylase activity (GO:0033749), oxidative RNA demethylase activity (GO:0035515), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), peptidyl-lysine 5-dioxygenase activity (GO:0070815), P-TEFb complex binding (GO:0106140), protein demethylase activity (GO:0140457), transcription regulator activator activity (GO:0140537), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-5 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
2-oxoglutarate-dependent dioxygenase activity	4
animal organ development	3
cellular anatomical structure	3
RNA processing	2
demethylase activity	2
catalytic activity, acting on a protein	2
nuclear lumen	2
renal system development	1
angiogenesis	1
chromatin organization	1
mRNA metabolic process	1
endocytosis	1
signal transduction	1
circulatory system development	1
peptidyl-lysine hydroxylation	1
respiratory tube development	1
respiratory system development	1
negative regulation of protein oligomerization	1
regulation of protein homooligomerization	1
protein homooligomerization	1
T cell differentiation	1
RNA modification	1
oxidative demethylation	1
myeloid leukocyte activation	1
phagocytosis, recognition	1
apoptotic cell clearance	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
mRNA splicing, via spliceosome	1
regulation of RNA splicing	1
regulation of mRNA processing	1
erythrocyte differentiation	1
myeloid cell development	1
protein complex oligomerization	1
nucleic acid binding	1
RNA binding	1

Protein interactions and networks

STRING

1586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
JMJD6	BRD4	O60885	979
JMJD6	U2AF2	P26368	975
JMJD6	NSD3	Q9BZ95	743
JMJD6	TIMD4	Q96H15	708
JMJD6	KDM8	Q8N371	690
JMJD6	BRD2	P25440	681
JMJD6	DEK	P35659	650
JMJD6	TYW5	A2RUC4	640
JMJD6	H4C7	Q99525	616
JMJD6	H4C16	P02304	613
JMJD6	CHD4	Q14839	603
JMJD6	U2AF1	Q01081	592
JMJD6	RIOX2	Q8IUF8	577
JMJD6	BRD3	Q15059	572
JMJD6	KDM4A	O75164	571

IntAct

139 interactions, top by confidence:

A	B	Type	Score
NOP10	DKC1	psi-mi:“MI:0914”(association)	0.890
MED11	MED19	psi-mi:“MI:0914”(association)	0.840
MED14	MED19	psi-mi:“MI:0914”(association)	0.790
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
BRD4	JMJD6	psi-mi:“MI:0915”(physical association)	0.780
BRD4	JMJD6	psi-mi:“MI:0407”(direct interaction)	0.780
JMJD6	BRD4	psi-mi:“MI:0915”(physical association)	0.780
JMJD6	BRD4	psi-mi:“MI:0407”(direct interaction)	0.780
ZRSR2	SF3B1	psi-mi:“MI:0914”(association)	0.730
JMJD6	NAA50	psi-mi:“MI:0915”(physical association)	0.720
NAA50	JMJD6	psi-mi:“MI:0915”(physical association)	0.720
CCNL1	JMJD6	psi-mi:“MI:0915”(physical association)	0.660
JMJD6	ESR1	psi-mi:“MI:0915”(physical association)	0.650
JMJD6	ESR1	psi-mi:“MI:0914”(association)	0.650
JMJD6	ESR1	psi-mi:“MI:2364”(proximity)	0.650
JMJD6	ESR1	psi-mi:“MI:0871”(demethylation reaction)	0.650
JMJD6	TP53	psi-mi:“MI:0914”(association)	0.640
JMJD6	TP53	psi-mi:“MI:0210”(hydroxylation reaction)	0.640
JMJD6	TP53	psi-mi:“MI:0915”(physical association)	0.640

BioGRID (342): NAA50 (Two-hybrid), FRMD6 (Two-hybrid), JMJD6 (Affinity Capture-RNA), JMJD6 (Affinity Capture-RNA), JMJD6 (Affinity Capture-RNA), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Affinity Capture-MS), JMJD6 (Co-fractionation)

ESM2 similar proteins: A2AV36, A2RSX7, A2RUC4, A3KP59, A8E534, B2GUS6, B5XF11, E1C7T6, O95801, P0C870, P0C872, P0CF52, P46952, P46953, P59723, Q08BV2, Q08BY5, Q0VCA8, Q0WVR4, Q29RJ2, Q3UDE2, Q3V3E1, Q4IER0, Q58CU3, Q58DS6, Q5EA24, Q5IH14, Q5R673, Q5R6G2, Q5ZHV5, Q5ZIB9, Q67XX3, Q67ZB6, Q6AXL5, Q6AYK2, Q6DIZ0, Q6NYC1, Q6P7I0, Q78JT3, Q8BFT6

Diamond homologs: Q08BY5, Q58DS6, Q5R6G2, Q5ZHV5, Q5ZMK5, Q623U2, Q67XX3, Q6AYK2, Q6GND3, Q6NYC1, Q6PFM0, Q6Q4H1, Q7ZX37, Q9ERI5, Q9GYI4, Q9H9V9, Q9M9E8, Q9VD28, Q9VJ97, O13977, Q60V67, Q5BKC6, Q8BFT6, Q3TA59, Q67ZB6, Q8BK58, Q96S16

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
JMJD6	“down-regulates activity”	MEPCE	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Adipogenesis	7	15.2×	1e-04
mRNA 3’-end processing	5	13.7×	2e-03
Respiratory Syncytial Virus Infection Pathway	5	13.7×	2e-03
ESR-mediated signaling	7	12.5×	2e-04
Regulation of lipid metabolism by PPARalpha	6	11.8×	1e-03
RSV-host interactions	5	10.9×	3e-03
Transcriptional regulation of white adipocyte differentiation	6	10.8×	1e-03
mRNA Splicing	7	10.7×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	8	23.8×	3e-07
RNA polymerase II preinitiation complex assembly	6	16.1×	2e-04
positive regulation of transcription initiation by RNA polymerase II	5	13.5×	3e-03
mRNA splicing, via spliceosome	12	10.9×	3e-07
RNA splicing	12	10.5×	3e-07
mRNA processing	8	6.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

842 predictions. Top by Δscore:

Variant	Effect	Δscore
17:76718856:TCGCA:T	acceptor_gain	1.0000
17:76718857:CGCA:C	acceptor_gain	1.0000
17:76718857:CGCAC:C	acceptor_gain	1.0000
17:76718858:GCA:G	acceptor_gain	1.0000
17:76718859:CA:C	acceptor_gain	1.0000
17:76718859:CAC:C	acceptor_gain	1.0000
17:76718861:C:CC	acceptor_gain	1.0000
17:76718862:T:A	acceptor_loss	1.0000
17:76718866:C:CT	acceptor_gain	1.0000
17:76718868:C:CT	acceptor_gain	1.0000
17:76718869:A:T	acceptor_gain	1.0000
17:76720354:CCTCA:C	donor_loss	1.0000
17:76720355:CTCA:C	donor_loss	1.0000
17:76720356:TCAC:T	donor_loss	1.0000
17:76720357:CACC:C	donor_loss	1.0000
17:76720358:A:C	donor_loss	1.0000
17:76720359:C:CT	donor_loss	1.0000
17:76720359:CCT:C	donor_gain	1.0000
17:76720494:AAATC:A	acceptor_gain	1.0000
17:76720495:AATC:A	acceptor_gain	1.0000
17:76720496:ATC:A	acceptor_gain	1.0000
17:76720496:ATCC:A	acceptor_loss	1.0000
17:76720496:ATCCT:A	acceptor_gain	1.0000
17:76720497:TC:T	acceptor_gain	1.0000
17:76720498:CC:C	acceptor_gain	1.0000
17:76720498:CCTGA:C	acceptor_loss	1.0000
17:76720499:C:CC	acceptor_gain	1.0000
17:76720499:C:T	acceptor_gain	1.0000
17:76720499:CTGAG:C	acceptor_loss	1.0000
17:76720500:T:C	acceptor_loss	1.0000

AlphaMissense

2666 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:76720493:A:G	L316S	1.000
17:76721805:A:G	W312R	1.000
17:76721805:A:T	W312R	1.000
17:76721824:T:A	R305S	1.000
17:76721824:T:G	R305S	1.000
17:76721825:C:A	R305I	1.000
17:76721825:C:G	R305T	1.000
17:76721826:T:C	R305G	1.000
17:76721839:C:A	K300N	1.000
17:76721839:C:G	K300N	1.000
17:76721846:C:G	W298S	1.000
17:76721847:A:G	W298R	1.000
17:76721847:A:T	W298R	1.000
17:76721875:A:C	F288L	1.000
17:76721875:A:T	F288L	1.000
17:76721877:A:G	F288L	1.000
17:76721878:A:C	N287K	1.000
17:76721878:A:T	N287K	1.000
17:76721880:T:C	N287D	1.000
17:76721880:T:G	N287H	1.000
17:76721885:G:A	T285I	1.000
17:76721891:G:T	A283D	1.000
17:76721892:C:G	A283P	1.000
17:76721908:A:C	N277K	1.000
17:76721908:A:T	N277K	1.000
17:76721915:A:T	V275D	1.000
17:76721918:A:T	V274D	1.000
17:76721920:A:C	H273Q	1.000
17:76721920:A:T	H273Q	1.000
17:76721921:T:C	H273R	1.000

dbSNP variants (sampled 300 via entrez): RS1000076924 (17:76725230 G>A,C), RS1000219700 (17:76716368 C>T), RS1000259948 (17:76725092 G>A,C), RS1000350478 (17:76727001 C>T), RS1000383467 (17:76726831 T>C,G), RS1000567446 (17:76721609 G>C), RS1000937872 (17:76720130 A>G), RS1001322368 (17:76724896 G>A), RS1001545113 (17:76715681 C>A), RS1001727432 (17:76721705 G>A), RS1001772584 (17:76716604 G>A,T), RS1002081479 (17:76722024 C>G,T), RS1002196956 (17:76719658 A>C), RS1002211918 (17:76725018 C>G,T), RS1002348789 (17:76714945 G>A)

Disease associations

OMIM: gene MIM:604914 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002071_2	Retinal arteriolar caliber	2.000000e-10
GCST90002398_313	Neutrophil count	2.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523345 (SINGLE PROTEIN), CHEMBL6066135 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

17 potent at pChembl≥5 of 27 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.32	Kd	48	nM	MOLIBRESIB
7.05	IC50	90	nM	MOLIBRESIB
6.66	IC50	220	nM	CHEMBL4443954
6.17	IC50	681	nM	CHEMBL4849961
6.11	IC50	780	nM	CHEMBL4878147
6.04	IC50	914	nM	CHEMBL4869715
5.95	IC50	1121	nM	CHEMBL4867354
5.87	IC50	1345	nM	CHEMBL4848239
5.84	IC50	1449	nM	CHEMBL4858652
5.77	IC50	1706	nM	CHEMBL4860023
5.73	IC50	1864	nM	CHEMBL4857134
5.71	IC50	1938	nM	CHEMBL4864428
5.61	IC50	2440	nM	CHEMBL4443954
5.61	IC50	2434	nM	CHEMBL4862155
5.60	IC50	2533	nM	CHEMBL4850682
5.42	IC50	3795	nM	CHEMBL4863495
5.25	IC50	5688	nM	CHEMBL4846736

PubChem BioAssay actives

17 with measured affinity, of 66 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179125: Binding affinity against JMJD6 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0480	uM
3-(3H-imidazo[4,5-c]pyridin-2-yl)-6-methylchromen-2-one	1520143: Inhibition of His-tagged JMJD6 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as decrease in demethylase activity by measuring release of formaldehyde using core histone as substrate preincubated with enzyme for 10 mins followed by incubation with substrate for 1 hr measured following 2 hrs incubation with ammonium acetate/acetoacetanilide by fluorescence based analysis	ic50	0.2200	uM
2,2,2-trifluoroethyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	0.6810	uM
2-[2-[(2-hydroxyphenyl)methylidene]hydrazinyl]-4-methyl-1H-pyrimidin-6-one	1776840: Inhibition of JMJD6 (unknown origin)	ic50	0.7800	uM
ethyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	0.9140	uM
2,2-difluoroethyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	1.1210	uM
propyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	1.3450	uM
2-fluoroethyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	1.4490	uM
2-(1-methylpyrazol-3-yl)pyridine-4-carboxylic acid	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	1.7060	uM
methyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	1.8640	uM
propan-2-yl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	1.9380	uM
ethyl 2-(1-ethylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	2.4340	uM
cyclobutylmethyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	2.5330	uM
cyclopropylmethyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	3.7950	uM
benzyl 2-(1-methylpyrazol-3-yl)pyridine-4-carboxylate	1776827: Inhibition of JMJD6 (unknown origin) by Succinate-Glo assay	ic50	5.6880	uM

CTD chemical–gene interactions

63 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	5
Arsenic	affects expression, affects methylation, increases abundance, increases expression	4
Valproic Acid	affects expression, increases expression	3
cobaltous chloride	increases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Formaldehyde	increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
tert-Butylhydroperoxide	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	increases abundance, increases expression	1
2-butenal	increases expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
ochratoxin A	increases expression	1
diethyl malate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
fenpyroximate	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1

ChEMBL screening assays

29 unique, capped per target: 29 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4316545	Binding	Inhibition of His-tagged JMJD6 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as increase in H4 arginine 3 symmetrical dimethylation (H4R3me2s) content at 10 uM using core histone as substrate preincubated with enzyme fo	In Silico Discovery of JMJD6 Inhibitors for Cancer Treatment. — ACS Med Chem Lett

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2ZH	Abcam HEK293T JMJD6 KO	Transformed cell line	Female
CVCL_B7XS	Abcam Raji JMJD6 KO	Cancer cell line	Male
CVCL_B9YH	Abcam THP-1 JMJD6 KO	Cancer cell line	Male
CVCL_C7A9	Abcam PC-3 JMJD6 KO	Cancer cell line	Male
CVCL_D7T0	Ubigene A-549 JMJD6 KO	Cancer cell line	Male
CVCL_ST79	HAP1 JMJD6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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