METTL4

Summary

METTL4 (methyltransferase 4, N6-adenosine, HGNC:24726) is a protein-coding gene on chromosome 18p11.32, encoding N(6)-adenine-specific methyltransferase METTL4 (Q8N3J2). N(6)-adenine-specific methyltransferase that can methylate both RNAs and DNA.

Enables RNA methyltransferase activity and site-specific DNA-methyltransferase (adenine-specific) activity. Involved in regulation of primary metabolic process and snRNA (adenine-N6)-methylation. Located in cytosol; mitochondrial matrix; and nucleus. Part of RNA N6-methyladenosine methyltransferase complex and oxidoreductase complex.

Source: NCBI Gene 64863 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 75 total — 1 likely-pathogenic
• MANE Select transcript: NM_022840

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24726
Approved symbol	METTL4
Name	methyltransferase 4, N6-adenosine
Location	18p11.32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23017, HsT661
Ensembl gene	ENSG00000101574
Ensembl biotype	protein_coding
OMIM	619626
Entrez	64863

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 retained_intron

ENST00000319888, ENST00000573134, ENST00000574538, ENST00000574676, ENST00000576251, ENST00000577166, ENST00000609769, ENST00000899468, ENST00000919555, ENST00000919556, ENST00000919557

RefSeq mRNA: 2 — MANE Select: NM_022840 NM_001308401, NM_022840

CCDS: CCDS11826, CCDS77144

Canonical transcript exons

ENST00000574538 — 9 exons

Exon	Start	End
ENSE00001279911	2552695	2552764
ENSE00001279937	2554669	2555038
ENSE00001331163	2566821	2567654
ENSE00002639315	2571149	2571505
ENSE00002657845	2537530	2539145
ENSE00003471582	2547355	2547529
ENSE00003585699	2544653	2544759
ENSE00003627834	2544195	2544286
ENSE00003646138	2563797	2563859

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 88.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.0579 / max 144.9108, expressed in 1783 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170971	9.0032	1775
170970	1.0547	660

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	88.33	gold quality
secondary oocyte	CL:0000655	86.23	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.96	gold quality
calcaneal tendon	UBERON:0003701	84.57	gold quality
ganglionic eminence	UBERON:0004023	82.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.87	gold quality
cortical plate	UBERON:0005343	80.60	gold quality
stromal cell of endometrium	CL:0002255	79.80	gold quality
granulocyte	CL:0000094	79.58	gold quality
spleen	UBERON:0002106	78.65	gold quality
islet of Langerhans	UBERON:0000006	78.53	gold quality
mucosa of transverse colon	UBERON:0004991	78.16	gold quality
lymph node	UBERON:0000029	78.13	gold quality
blood	UBERON:0000178	78.09	gold quality
rectum	UBERON:0001052	78.01	gold quality
bone marrow cell	CL:0002092	77.98	gold quality
body of uterus	UBERON:0009853	77.96	gold quality
tonsil	UBERON:0002372	77.71	gold quality
vermiform appendix	UBERON:0001154	77.45	gold quality
lower esophagus mucosa	UBERON:0035834	77.07	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.95	gold quality
vagina	UBERON:0000996	76.81	gold quality
omental fat pad	UBERON:0010414	76.79	gold quality
left ovary	UBERON:0002119	76.74	gold quality
peritoneum	UBERON:0002358	76.69	gold quality
right ovary	UBERON:0002118	76.67	gold quality
endocervix	UBERON:0000458	76.45	gold quality
ectocervix	UBERON:0012249	76.44	gold quality
adipose tissue of abdominal region	UBERON:0007808	76.41	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting METTL4, 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-4531	99.99	69.70	3181
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4698	99.84	71.41	4303

Literature-anchored findings (GeneRIF, showing 7)

• associations revealed between genetic polymorphisms located in the flanking region of the ARID1B genes and hypoesthesia (PMID:23834954)
• For the methylation of adenosine in RNA, Mettl3 is the catalytically active subunit, while Mettl14 plays a structural role critical for substrate recognition. (PMID:27373337)
• METTL4 is an snRNA m(6)Am methyltransferase that regulates RNA splicing. (PMID:31913360)
• N(6)-Deoxyadenosine Methylation in Mammalian Mitochondrial DNA. (PMID:32183942)
• METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing. (PMID:32813009)
• METTL4 methylates U2 snRNA Am at position 30 to generate m6Am in vivo. ‘HMAGKD’, where H = A/C/U, M = A/C, K = G/U, D = A/G/U, and A is the methylation site, is METTL4’s in vivo preferred target motif. (PMID:32813009)
• N-6-Methyladenosine in Vasoactive microRNAs during Hypoxia; A Novel Role for METTL4. (PMID:35162982)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mettl4	ENSDARG00000088999
mus_musculus	Mettl4	ENSMUSG00000055660
rattus_norvegicus	Mettl4	ENSRNOG00000026280
drosophila_melanogaster	Mettl4	FBGN0015351
caenorhabditis_elegans		WBGENE00015939

Protein

Protein identifiers

N(6)-adenine-specific methyltransferase METTL4 — Q8N3J2 (reviewed: Q8N3J2)

Alternative names: Methyltransferase-like protein 4, N(6)-adenine-specific DNA methyltransferase METTL4, snRNA (2’-O-methyladenosine-N(6)-)-methyltransferase METTL4

All UniProt accessions (6): Q8N3J2, I3L0Y1, I3L3W2, I3L4A0, J3KNJ7, V9GYU3

UniProt curated annotations — full annotation on UniProt →

Function. N(6)-adenine-specific methyltransferase that can methylate both RNAs and DNA. Acts as a N(6)-adenine-specific RNA methyltransferase by catalyzing formation of N6,2’-O-dimethyladenosine (m6A(m)) on internal positions of U2 small nuclear RNA (snRNA): methylates the 6th position of adenine residues with a pre-deposited 2’-O-methylation. Internal m6A(m) methylation of snRNAs regulates RNA splicing. Also able to act as a N(6)-adenine-specific DNA methyltransferase by mediating methylation of DNA on the 6th position of adenine (N(6)-methyladenosine). The existence of N(6)-methyladenosine (m6A) on DNA is however unclear in mammals, and additional evidences are required to confirm the role of the N(6)-adenine-specific DNA methyltransferase activity of METTL4 in vivo. Acts as a regulator of mitochondrial transcript levels and mitochondrial DNA (mtDNA) copy number by mediating mtDNA N(6)-methylation: m6A on mtDNA reduces transcription by repressing TFAM DNA-binding and bending. N(6)-methyladenosine deposition by METTL4 regulates Polycomb silencing by triggering ubiquitination and degradation of sensor proteins ASXL1 and MPND, leading to inactivation of the PR-DUB complex and subsequent preservation of Polycomb silencing.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Mitochondrion matrix.

Similarity. Belongs to the MT-A70-like family.

RefSeq proteins (2): NP_001295330, NP_073751* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002052	DNA_methylase_N6_adenine_CS	Conserved_site
IPR007757	MT-A70-like	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF05063

Catalyzed reactions (Rhea), 2 shown:

• a 2’-deoxyadenosine in DNA + S-adenosyl-L-methionine = an N(6)-methyl-2’-deoxyadenosine in DNA + S-adenosyl-L-homocysteine + H(+) (RHEA:15197)
• a 2’-O-methyladenosine in U2 snRNA + S-adenosyl-L-methionine = an N(6)-methyl-2’-O-methyladenosine in U2 snRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:62672)

UniProt features (8 total): sequence variant 5, chain 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N3J2-F1	77.91	0.53

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
287–290	abolished methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_RNA_MODIFICATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, FISCHER_G2_M_CELL_CYCLE, ZIC1_01, GOBP_RNA_SPLICING, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, DING_LUNG_CANCER_EXPRESSION_BY_COPY_NUMBER, FISCHER_DREAM_TARGETS, GOBP_CHROMATIN_REMODELING

GO Biological Process (7): methylation (GO:0032259), regulation of RNA splicing (GO:0043484), negative regulation of gene expression, epigenetic (GO:0045814), regulation of mitochondrial DNA replication (GO:0090296), snRNA (adenine-N6)-methylation (GO:0120049), regulation of mitochondrial transcription (GO:1903108), chromatin organization (GO:0006325)

GO Molecular Function (8): nucleic acid binding (GO:0003676), RNA methyltransferase activity (GO:0008173), site-specific DNA-methyltransferase (adenine-specific) activity (GO:0009007), U2 snRNA (2’-O-methyladenosine-N6)-methyltransferase activity (GO:0106347), methyltransferase activity (GO:0008168), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), transferase activity (GO:0016740), catalytic activity, acting on a nucleic acid (GO:0140640)

GO Cellular Component (7): nucleus (GO:0005634), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), RNA N6-methyladenosine methyltransferase complex (GO:0036396), cytoplasm (GO:0005737), mitochondrion (GO:0005739), oxidoreductase complex (GO:1990204)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
methyltransferase activity	2
catalytic activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cellular anatomical structure	2
metabolic process	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
mitochondrial DNA replication	1
regulation of DNA-templated DNA replication	1
regulation of mitochondrial DNA metabolic process	1
snRNA modification	1
regulation of DNA-templated transcription	1
mitochondrial transcription	1
regulation of mitochondrial gene expression	1
cellular component organization	1
binding	1
catalytic activity, acting on RNA	1
S-adenosylmethionine-dependent methyltransferase activity	1
DNA-methyltransferase activity	1
snRNA methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
mitochondrion	1
intracellular organelle lumen	1
methyltransferase complex	1
intracellular anatomical structure	1
catalytic complex	1

Protein interactions and networks

STRING

674 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
METTL4	METTL3	Q86U44	999
METTL4	WTAP	Q15007	994
METTL4	METTL14	Q9HCE5	992
METTL4	VIRMA	Q69YN4	942
METTL4	RBM15	Q96T37	859
METTL4	HEMK2	Q9Y5N5	734
METTL4	METTL16	Q86W50	724
METTL4	ALKBH1	Q13686	709
METTL4	ALKBH5	Q6P6C2	700
METTL4	ALKBH4	Q9NXW9	667
METTL4	FTO	Q9C0B1	641
METTL4	PCIF1	Q9H4Z3	624
METTL4	YTHDF1	Q9BYJ9	613
METTL4	METTL5	Q9NRN9	612
METTL4	YTHDF2	Q9Y5A9	600

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A3Q2TTB3, A0JMR6, A1L3F5, A4IIA7, A5WW08, A6NHR9, A9JRL3, F4HZK4, O17482, O95876, P79457, Q0P410, Q12789, Q149N8, Q3B7T1, Q3TTL0, Q3U034, Q3UD82, Q3ULM0, Q4R3W5, Q4R683, Q4R6C7, Q4R7Q1, Q5FWP4, Q5R5T0, Q5R9R1, Q5RAX4, Q5T8I9, Q5ZJ87, Q66J91, Q69Z66, Q6GQV7, Q6NVF4, Q6P256, Q6P5D8, Q7Z2T5, Q8BMD5, Q8BXK4, Q8C0W1, Q8IY21

Diamond homologs: A0A9P5CQV5, G4MSY9, Q09800, Q09956, Q3U034, Q8LFA9, Q8N3J2, Q6EU10

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	57
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2151240	NM_022840.5(METTL4):c.829+1G>A	Likely pathogenic

SpliceAI

1969 predictions. Top by Δscore:

Variant	Effect	Δscore
18:2547353:A:AC	donor_gain	1.0000
18:2547354:C:CC	donor_gain	1.0000
18:2547410:T:TA	donor_gain	1.0000
18:2552761:CTAT:C	acceptor_gain	1.0000
18:2552762:TAT:T	acceptor_gain	1.0000
18:2552765:C:CC	acceptor_gain	1.0000
18:2563876:T:TC	acceptor_gain	1.0000
18:2566873:T:TA	donor_gain	1.0000
18:2539144:CT:C	acceptor_gain	0.9900
18:2547411:C:A	donor_gain	0.9900
18:2552687:CCACT:C	donor_loss	0.9900
18:2552688:CACTT:C	donor_loss	0.9900
18:2552689:ACTT:A	donor_loss	0.9900
18:2552690:CT:C	donor_loss	0.9900
18:2552691:TTAC:T	donor_loss	0.9900
18:2552692:T:TA	donor_loss	0.9900
18:2552693:A:AC	donor_gain	0.9900
18:2552693:A:AG	donor_loss	0.9900
18:2552694:C:A	donor_loss	0.9900
18:2552694:C:CC	donor_gain	0.9900
18:2552763:AT:A	acceptor_gain	0.9900
18:2552765:CTGA:C	acceptor_loss	0.9900
18:2554667:A:AC	donor_gain	0.9900
18:2554668:C:CC	donor_gain	0.9900
18:2554668:CA:C	donor_gain	0.9900
18:2554803:T:TA	donor_gain	0.9900
18:2563855:CGCTT:C	acceptor_gain	0.9900
18:2563873:CAAT:C	acceptor_gain	0.9900
18:2563876:T:C	acceptor_gain	0.9900
18:2566823:T:A	donor_gain	0.9900

AlphaMissense

3127 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:2544208:C:A	K420N	0.998
18:2544208:C:G	K420N	0.998
18:2544235:G:C	S411R	0.998
18:2544235:G:T	S411R	0.998
18:2544237:T:G	S411R	0.998
18:2547363:A:G	W356R	0.998
18:2547363:A:T	W356R	0.998
18:2547369:A:G	W354R	0.998
18:2547369:A:T	W354R	0.998
18:2547450:A:G	W327R	0.998
18:2547450:A:T	W327R	0.998
18:2552726:A:G	W290R	0.998
18:2552726:A:T	W290R	0.998
18:2539065:A:G	W452R	0.997
18:2539065:A:T	W452R	0.997
18:2544210:T:C	K420E	0.997
18:2539061:C:A	G453V	0.996
18:2539066:A:C	S451R	0.996
18:2539066:A:T	S451R	0.996
18:2539068:T:G	S451R	0.996
18:2544209:T:G	K420T	0.996
18:2552734:T:C	D287G	0.996
18:2539091:C:G	R443P	0.995
18:2539096:A:C	F441L	0.995
18:2539096:A:T	F441L	0.995
18:2539098:A:G	F441L	0.995
18:2547361:C:A	W356C	0.995
18:2547361:C:G	W356C	0.995
18:2547448:C:A	W327C	0.995
18:2547448:C:G	W327C	0.995

dbSNP variants (sampled 300 via entrez): RS1000138505 (18:2572914 A>G), RS1000155953 (18:2553962 A>C), RS1000182831 (18:2545341 T>A), RS1000351302 (18:2548755 C>T), RS1000363345 (18:2542327 G>T), RS1000397669 (18:2542383 A>G,T), RS1000423907 (18:2541914 C>T), RS1000499740 (18:2572885 C>T), RS1000504333 (18:2553988 A>G), RS1000598463 (18:2571477 A>G), RS1000731906 (18:2543558 C>A,G,T), RS1000751330 (18:2548954 A>G), RS1000758289 (18:2540440 T>C), RS1000932409 (18:2560250 T>C), RS1000983702 (18:2566407 G>A)

Disease associations

OMIM: gene MIM:619626 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002579_32	Heschl’s gyrus morphology	7.000000e-06
GCST004748_7	Lung cancer	3.000000e-06
GCST004796_4	Brain volume in infants (cerebrospinal fluid)	8.000000e-07
GCST007576_254	Chronotype	4.000000e-11
GCST008361_4	Response to cognitive-behavioural therapy in major depressive disorder	3.000000e-06
GCST008555_1	Breakfast cereal skipping frequency	2.000000e-17
GCST008556_1	Breakfast skipping	2.000000e-17
GCST009144_8	Disease progression in age-related macular degeneration (adjusted for baseline)	3.000000e-06
GCST010397_95	Gut microbiota (bacterial taxa, rank normal transformation method)	4.000000e-08
GCST010988_70	Adult body size	7.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0007820	cognitive behavioural therapy
EFO:0010129	breakfast skipping measurement
EFO:0008336	disease progression measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
(+)-JQ1 compound	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cobalt	decreases expression	1
Doxorubicin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
Zinc	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XQ46	HAP1 METTL4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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