ALKBH4

Summary

ALKBH4 (alkB homolog 4, lysine demethylase, HGNC:21900) is a protein-coding gene on chromosome 7q22.1, encoding Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (Q9NXW9). Dioxygenase that mediates demethylation of actin monomethylated at ‘Lys-84’ (K84me1), thereby acting as a regulator of actomyosin-processes.

Enables 2-oxoglutarate-dependent dioxygenase activity and actin binding activity. Involved in actomyosin structure organization and cleavage furrow ingression. Located in contractile ring and midbody.

Source: NCBI Gene 54784 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 81 total — 2 pathogenic
• MANE Select transcript: NM_017621

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21900
Approved symbol	ALKBH4
Name	alkB homolog 4, lysine demethylase
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20013
Ensembl gene	ENSG00000160993
Ensembl biotype	protein_coding
OMIM	613302
Entrez	54784

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000292566, ENST00000490528, ENST00000498283, ENST00000881811

RefSeq mRNA: 1 — MANE Select: NM_017621 NM_017621

CCDS: CCDS5723

Canonical transcript exons

ENST00000292566 — 3 exons

Exon	Start	End
ENSE00001055853	102459604	102459801
ENSE00001177954	102456238	102457981
ENSE00001919176	102464714	102464863

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 84.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.8612 / max 52.2440, expressed in 1736 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85355	7.8612	1736

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	84.76	silver quality
type B pancreatic cell	CL:0000169	84.60	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.19	gold quality
prefrontal cortex	UBERON:0000451	83.46	gold quality
granulocyte	CL:0000094	82.41	gold quality
olfactory bulb	UBERON:0002264	81.58	silver quality
cerebellar hemisphere	UBERON:0002245	81.27	gold quality
cerebellar cortex	UBERON:0002129	81.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.09	gold quality
cerebellum	UBERON:0002037	80.51	gold quality
tongue squamous epithelium	UBERON:0006919	80.42	silver quality
cortical plate	UBERON:0005343	80.38	gold quality
right frontal lobe	UBERON:0002810	79.98	gold quality
frontal cortex	UBERON:0001870	79.88	gold quality
cingulate cortex	UBERON:0003027	79.81	gold quality
anterior cingulate cortex	UBERON:0009835	79.80	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.73	gold quality
neocortex	UBERON:0001950	79.45	gold quality
blood	UBERON:0000178	79.16	gold quality
oocyte	CL:0000023	78.97	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.83	gold quality
stromal cell of endometrium	CL:0002255	78.70	gold quality
right adrenal gland	UBERON:0001233	78.59	gold quality
right adrenal gland cortex	UBERON:0035827	78.42	gold quality
ganglionic eminence	UBERON:0004023	78.11	gold quality
spleen	UBERON:0002106	78.07	gold quality
gastrocnemius	UBERON:0001388	77.92	gold quality
nucleus accumbens	UBERON:0001882	77.86	gold quality
mucosa of transverse colon	UBERON:0004991	77.81	gold quality
right lobe of thyroid gland	UBERON:0001119	77.77	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting ALKBH4, 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-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-367-5P	98.84	67.18	902
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-744-3P	97.99	67.76	637
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-6501-5P	97.41	68.24	712
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-3674	97.01	68.86	1171
HSA-MIR-505-5P	97.01	65.54	778
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-5702	96.68	68.21	958
HSA-MIR-642B-5P	96.37	67.26	745
HSA-MIR-1258	96.08	67.74	700

Literature-anchored findings (GeneRIF, showing 6)

• ALKBH4 represents an active Fe(II)/2OG-dependent decarboxylase and suggest that the cysteine cluster is involved in processes other than Fe co-ordination. (PMID:21166655)
• The regions mediating binding to ALKBH4 comprised domains previously reported to be involved in interaction with DNA or chromatin. (PMID:23145062)
• ALKBH4-dependent actin demethylation regulates actomyosin function by promoting actin-non-muscle myosin II interaction. (PMID:23673617)
• ALKBH4 promotes tumourigenesis with a poor prognosis in non-small-cell lung cancer. (PMID:33883577)
• Quantitative proteomics revealed new functions of ALKBH4. (PMID:34951099)
• ALKBH4 is a novel enzyme that promotes translation through modified uridine regulation. (PMID:37507018)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alkbh4	ENSDARG00000052247
mus_musculus	Alkbh4	ENSMUSG00000039754
rattus_norvegicus	Alkbh4	ENSRNOG00000001428
drosophila_melanogaster	CG4036	FBGN0032149
caenorhabditis_elegans		WBGENE00017304

Protein

Protein identifiers

Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 — Q9NXW9 (reviewed: Q9NXW9)

Alternative names: Alkylated DNA repair protein alkB homolog 4, DNA N6-methyl adenine demethylase ALKBH4, Lysine-specific demethylase ALKBH4

All UniProt accessions (1): Q9NXW9

UniProt curated annotations — full annotation on UniProt →

Function. Dioxygenase that mediates demethylation of actin monomethylated at ‘Lys-84’ (K84me1), thereby acting as a regulator of actomyosin-processes. Demethylation of actin K84me1 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration. In addition to proteins, also demethylates DNA: specifically demethylates DNA methylated on the 6th position of adenine (N(6)-methyladenosine) DNA, thereby regulating Polycomb silencing.

Subunit / interactions. Interacts with ZFHX3, MLLT3, MLLT1, HSF4, EP300, TES, EIF3C, MTMR6 and PSMA6.

Subcellular location. Cytoplasm. Nucleus. Nucleolus. Midbody.

Tissue specificity. Widely expressed, with highest expression in pancreas, ovary and spleen.

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

Miscellaneous. Actin demethylase activity has not been directly confirmed in vitro; however a number of experiments strongly suggest that ALKBH4 acts as a protein demethylase. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the alkB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NXW9-1	1	yes
Q9NXW9-2	2

RefSeq proteins (1): NP_060091* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR032857	ALKBH4	Family
IPR037151	AlkB-like_sf	Homologous_superfamily

Catalyzed reactions (Rhea), 2 shown:

• an N(6)-methyl-2’-deoxyadenosine in DNA + 2-oxoglutarate + O2 = a 2’-deoxyadenosine in DNA + formaldehyde + succinate + CO2 (RHEA:49524)
• N(6)-methyl-L-lysyl-[protein] + 2-oxoglutarate + O2 = L-lysyl-[protein] + formaldehyde + succinate + CO2 (RHEA:60924)

UniProt features (16 total): binding site 4, mutagenesis site 3, splice variant 2, modified residue 2, initiator methionine 1, chain 1, sequence variant 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXW9-F1	90.14	0.78

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 (4): 169; 171; 254; 265

Post-translational modifications (2): 2, 8

Mutagenesis-validated functional residues (3):

Position	Phenotype
169	loss of function mutant that acts as a dominant-negative mutant when overexpressed, leading to multinucleation and cleav
171	loss of function mutant that acts as a dominant-negative mutant when overexpressed, leading to multinucleation and cleav
254	loss of function mutant that acts as a dominant-negative mutant when overexpressed, leading to multinucleation and cleav

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 121 (showing top): RRAGTTGT_UNKNOWN, MODULE_255, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, MODULE_317, GOBP_CYTOKINETIC_PROCESS, GOBP_DEMETHYLATION, GOBP_CYTOKINESIS, GOBP_ACTOMYOSIN_STRUCTURE_ORGANIZATION, GOMF_ACTIN_BINDING, GOBP_MEMBRANE_ORGANIZATION, GOBP_MEMBRANE_INVAGINATION, GOBP_CHROMATIN_REMODELING

GO Biological Process (5): actomyosin structure organization (GO:0031032), cleavage furrow ingression (GO:0036090), demethylation (GO:0070988), positive regulation of gene expression, epigenetic (GO:0141137), chromatin organization (GO:0006325)

GO Molecular Function (10): actin binding (GO:0003779), 2-oxoglutarate-dependent dioxygenase activity (GO:0016706), demethylase activity (GO:0032451), broad specificity oxidative DNA demethylase activity (GO:0035516), metal ion binding (GO:0046872), protein demethylase activity (GO:0140457), DNA N6-methyladenine demethylase activity (GO:0141131), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), dioxygenase activity (GO:0051213)

GO Cellular Component (5): nucleolus (GO:0005730), cytoplasm (GO:0005737), midbody (GO:0030496), contractile ring (GO:0070938), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
catalytic activity	2
2-oxoglutarate-dependent dioxygenase activity	2
DNA demethylase activity	2
actin cytoskeleton organization	1
cytokinetic process	1
cytoskeleton-dependent cytokinesis	1
plasma membrane invagination	1
metabolic process	1
positive regulation of gene expression	1
epigenetic regulation of gene expression	1
cellular component organization	1
cytoskeletal protein binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
dioxygenase activity	1
cation binding	1
demethylase activity	1
catalytic activity, acting on a protein	1
binding	1
oxidoreductase activity	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

620 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALKBH4	ALKBH1	Q13686	953
ALKBH4	JMJD4	Q9H9V9	870
ALKBH4	ALKBH6	Q3KRA9	854
ALKBH4	ALKBH7	Q9BT30	852
ALKBH4	ALKBH2	Q6NS38	756
ALKBH4	ALKBH8	Q96BT7	755
ALKBH4	ALKBH3	Q96Q83	669
ALKBH4	METTL4	Q8N3J2	667
ALKBH4	HEMK2	Q9Y5N5	666
ALKBH4	ALKBH5	Q6P6C2	589
ALKBH4	FTO	Q9C0B1	553
ALKBH4	HEMK1	Q9Y5R4	543
ALKBH4	D2HGDH	Q8N465	459
ALKBH4	KLHL31	Q9H511	443
ALKBH4	EP300	Q09472	421

IntAct

66 interactions, top by confidence:

A	B	Type	Score
DTX2	ALKBH4	psi-mi:“MI:0915”(physical association)	0.830
ALKBH4	DTX2	psi-mi:“MI:0915”(physical association)	0.830
MLLT3	ALKBH4	psi-mi:“MI:0915”(physical association)	0.680
ALKBH4	MLLT3	psi-mi:“MI:0403”(colocalization)	0.680
TRAF4	ALKBH4	psi-mi:“MI:0915”(physical association)	0.670
TCF4	ALKBH4	psi-mi:“MI:0915”(physical association)	0.560
NIF3L1	ALKBH4	psi-mi:“MI:0915”(physical association)	0.560
BPIFA1	ALKBH4	psi-mi:“MI:0915”(physical association)	0.560
LCN2	ALKBH4	psi-mi:“MI:0915”(physical association)	0.560
FAM168A	ALKBH4	psi-mi:“MI:0915”(physical association)	0.560
TXNL4B	ALKBH4	psi-mi:“MI:0915”(physical association)	0.560
GORASP2	ALKBH4	psi-mi:“MI:0915”(physical association)	0.560
EP300	ALKBH4	psi-mi:“MI:0915”(physical association)	0.440
ALKBH4	MLLT1	psi-mi:“MI:0915”(physical association)	0.440
MLLT1	ALKBH4	psi-mi:“MI:0403”(colocalization)	0.440
EP300	ALKBH4	psi-mi:“MI:0403”(colocalization)	0.440

BioGRID (37): ALKBH4 (Two-hybrid), DTX2 (Two-hybrid), ALKBH4 (Two-hybrid), ZFHX3 (Two-hybrid), MLLT3 (Two-hybrid), MLLT1 (Two-hybrid), HSF4 (Two-hybrid), EP300 (Two-hybrid), TES (Two-hybrid), EIF3C (Two-hybrid), MTMR6 (Two-hybrid), PSMA6 (Two-hybrid), ALKBH4 (Two-hybrid), ALKBH4 (Two-hybrid), ALKBH4 (Two-hybrid)

ESM2 similar proteins: A1L134, A4D1U4, A5A779, D3ZUM2, G5E872, I3L5V6, O09175, O35465, P55345, P56201, P70295, Q0PGW2, Q27J81, Q32M88, Q3B7U9, Q3UHG7, Q496Y0, Q5D0E6, Q5E9Y6, Q5EA80, Q5EBM0, Q5M868, Q5NDE9, Q5NVK5, Q5QJC3, Q69ZF3, Q6AYG3, Q6PDS3, Q6SZW1, Q8BGW4, Q8BYH7, Q8CHW4, Q8CIY2, Q8HZK3, Q8TD43, Q8VCT3, Q920N2, Q9BG99, Q9D2Q2, Q9H4A4

Diamond homologs: Q8MNT9, Q9D8F1, Q9NXW9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	69
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
57092	GRCh38/hg38 7q22.1-22.3(chr7:101525795-105432462)x3	Pathogenic
57255	GRCh38/hg38 7q22.1-31.1(chr7:101807149-112414850)x1	Pathogenic

SpliceAI

388 predictions. Top by Δscore:

Variant	Effect	Δscore
7:102457977:TAGTC:T	acceptor_gain	1.0000
7:102457978:AGTC:A	acceptor_gain	1.0000
7:102457979:GTC:G	acceptor_gain	1.0000
7:102457979:GTCC:G	acceptor_loss	1.0000
7:102457980:TC:T	acceptor_gain	1.0000
7:102457981:CC:C	acceptor_gain	1.0000
7:102457981:CCT:C	acceptor_loss	1.0000
7:102457982:C:CC	acceptor_gain	1.0000
7:102457989:A:AC	acceptor_gain	1.0000
7:102457989:A:C	acceptor_gain	1.0000
7:102459599:TCTAC:T	donor_loss	1.0000
7:102459600:CTACC:C	donor_loss	1.0000
7:102459601:TAC:T	donor_loss	1.0000
7:102459602:AC:A	donor_loss	1.0000
7:102459603:CC:C	donor_loss	1.0000
7:102459603:CCTG:C	donor_gain	1.0000
7:102459609:T:TA	donor_gain	1.0000
7:102459633:T:TA	donor_gain	1.0000
7:102457982:C:T	acceptor_gain	0.9900
7:102457983:T:C	acceptor_loss	0.9900
7:102457996:C:CT	acceptor_gain	0.9900
7:102457997:A:T	acceptor_gain	0.9900
7:102459606:G:A	donor_gain	0.9900
7:102459798:TTTT:T	acceptor_gain	0.9900
7:102459802:C:CC	acceptor_gain	0.9900
7:102464708:CCTTA:C	donor_loss	0.9900
7:102464709:CTTAC:C	donor_loss	0.9900
7:102464710:TTACC:T	donor_loss	0.9900
7:102464711:TAC:T	donor_loss	0.9900
7:102464712:A:AC	donor_gain	0.9900

AlphaMissense

1931 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:102459607:C:A	K106N	0.995
7:102459607:C:G	K106N	0.995
7:102457549:A:G	W252R	0.993
7:102457549:A:T	W252R	0.993
7:102457907:G:C	S132R	0.993
7:102457907:G:T	S132R	0.993
7:102457909:T:G	S132R	0.993
7:102457958:A:C	F115L	0.993
7:102457958:A:T	F115L	0.993
7:102457960:A:G	F115L	0.993
7:102457777:A:G	W176R	0.990
7:102457777:A:T	W176R	0.990
7:102459636:A:G	W97R	0.990
7:102459636:A:T	W97R	0.990
7:102457757:G:C	S182R	0.989
7:102457757:G:T	S182R	0.989
7:102457759:T:G	S182R	0.989
7:102457974:C:T	G110D	0.989
7:102459604:C:A	Q107H	0.989
7:102459604:C:G	Q107H	0.989
7:102459617:C:T	G103E	0.989
7:102457775:C:A	W176C	0.988
7:102457775:C:G	W176C	0.988
7:102457959:A:G	F115S	0.988
7:102459609:T:C	K106E	0.988
7:102459614:C:G	R104P	0.988
7:102457751:G:C	N184K	0.987
7:102457751:G:T	N184K	0.987
7:102457838:G:C	N155K	0.986
7:102457838:G:T	N155K	0.986

dbSNP variants (sampled 300 via entrez): RS1000046552 (7:102463744 T>C), RS1000372630 (7:102457943 T>C), RS1000835520 (7:102455848 C>G), RS1001022945 (7:102461062 C>T), RS1001262173 (7:102466472 T>C), RS1002025304 (7:102462369 CT>C), RS1002055151 (7:102462687 C>CT), RS1002390196 (7:102465153 A>C,T), RS1002398149 (7:102458763 A>G,T), RS1002773779 (7:102456580 G>A,C), RS1002910109 (7:102456411 C>A), RS1003029816 (7:102463670 G>A), RS1003318430 (7:102466666 C>A,T), RS1003358679 (7:102458340 C>G), RS1003876464 (7:102462593 C>G)

Disease associations

OMIM: gene MIM:613302 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007565_121	Morning person	3.000000e-23

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation, affects cotreatment	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
abrine	decreases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Copper	affects binding, decreases expression	1
Doxorubicin	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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