ZCCHC4

Summary

ZCCHC4 (zinc finger CCHC-type containing 4, HGNC:22917) is a protein-coding gene on chromosome 4p15.2, encoding rRNA N(6)-adenosine-methyltransferase ZCCHC4 (Q9H5U6). rRNA N6-methyltransferase that specifically methylates the adenine in position 4220 of 28S rRNA.

Enables S-adenosyl-L-methionine binding activity; rRNA (adenine-N6-)-methyltransferase activity; and zinc ion binding activity. Involved in positive regulation of translation and rRNA methylation. Located in cytoplasm and nucleolus.

Source: NCBI Gene 29063 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 109 total
• MANE Select transcript: NM_024936

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22917
Approved symbol	ZCCHC4
Name	zinc finger CCHC-type containing 4
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC052, FLJ23024, ZGRF4
Ensembl gene	ENSG00000168228
Ensembl biotype	protein_coding
OMIM	611792
Entrez	29063

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000302874, ENST00000505412, ENST00000505451, ENST00000507760, ENST00000508058, ENST00000904257, ENST00000931732, ENST00000931733

RefSeq mRNA: 2 — MANE Select: NM_024936 NM_001318148, NM_024936

CCDS: CCDS43218

Canonical transcript exons

ENST00000302874 — 13 exons

Exon	Start	End
ENSE00001766877	25365022	25365166
ENSE00001767779	25369029	25370383
ENSE00002040802	25312774	25312936
ENSE00003468245	25364454	25364505
ENSE00003501870	25349492	25349642
ENSE00003550497	25362226	25362301
ENSE00003571386	25315318	25315400
ENSE00003608316	25333908	25333988
ENSE00003614966	25361859	25361980
ENSE00003655007	25314046	25314164
ENSE00003665658	25345548	25345620
ENSE00003669231	25351589	25351689
ENSE00003682837	25333183	25333458

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 83.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9900 / max 110.0044, expressed in 1771 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47128	7.9900	1771

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.55	gold quality
gastrocnemius	UBERON:0001388	80.43	gold quality
calcaneal tendon	UBERON:0003701	80.34	gold quality
muscle of leg	UBERON:0001383	80.28	gold quality
ventricular zone	UBERON:0003053	80.05	gold quality
stromal cell of endometrium	CL:0002255	79.08	gold quality
colonic epithelium	UBERON:0000397	78.64	gold quality
body of uterus	UBERON:0009853	77.79	gold quality
right adrenal gland cortex	UBERON:0035827	77.65	gold quality
right adrenal gland	UBERON:0001233	77.32	gold quality
left uterine tube	UBERON:0001303	77.26	gold quality
apex of heart	UBERON:0002098	77.25	gold quality
ganglionic eminence	UBERON:0004023	77.14	gold quality
tibial nerve	UBERON:0001323	76.73	gold quality
ectocervix	UBERON:0012249	76.66	gold quality
left ovary	UBERON:0002119	76.54	gold quality
left adrenal gland	UBERON:0001234	76.52	gold quality
islet of Langerhans	UBERON:0000006	76.50	gold quality
popliteal artery	UBERON:0002250	76.40	gold quality
tibial artery	UBERON:0007610	76.40	gold quality
right ovary	UBERON:0002118	76.33	gold quality
left adrenal gland cortex	UBERON:0035825	76.16	gold quality
rectum	UBERON:0001052	76.04	gold quality
body of pancreas	UBERON:0001150	76.00	gold quality
muscle layer of sigmoid colon	UBERON:0035805	76.00	gold quality
aorta	UBERON:0000947	75.90	gold quality
metanephros cortex	UBERON:0010533	75.88	gold quality
sural nerve	UBERON:0015488	75.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting ZCCHC4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-4297	98.77	66.95	2013

Literature-anchored findings (GeneRIF, showing 6)

• ZCCHC4 protein is overexpressed in hepatocellular carcinoma tumors.ZCCHC4 is an m6A RNA methyltransferase. (PMID:30531910)
• 3.1 A-resolution crystal structure of human CCHC zinc finger-containing protein ZCCHC4, a 28S rRNA-specific m(6)A methyltransferase, bound to S-adenosyl-L-homocysteine. Mutational and enzymatic analyses further substantiate the molecular basis for ZCCHC4-RNA recognition and a role of the stem-loop structure within substrate in governing the substrate specificity. (PMID:31695039)
• In summary, we establish ZCCHC4 as the enzyme responsible for m6A modification of human 28S rRNA, and demonstrate its functional significance in mRNA translation. (PMID:31799605)
• RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis. (PMID:35853866)
• ZCCHC4 Promotes Osteosarcoma Progression by Upregulating ITGB1. (PMID:37606162)
• The epigenetic downregulation of LncGHRLOS mediated by RNA m6A methylase ZCCHC4 promotes colorectal cancer tumorigenesis. (PMID:38326863)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	zcchc4	ENSDARG00000104531
mus_musculus	Zcchc4	ENSMUSG00000029179
rattus_norvegicus	Zcchc4	ENSRNOG00000029064
drosophila_melanogaster	CG12863	FBGN0033948
caenorhabditis_elegans		WBGENE00009352

Protein

Protein identifiers

rRNA N(6)-adenosine-methyltransferase ZCCHC4 — Q9H5U6 (reviewed: Q9H5U6)

Alternative names: Zinc finger CCHC domain-containing protein 4

All UniProt accessions (2): Q9H5U6, H0Y8V8

UniProt curated annotations — full annotation on UniProt →

Function. rRNA N6-methyltransferase that specifically methylates the adenine in position 4220 of 28S rRNA. N6-methylation of adenine(4220) in 28S rRNA is required for translation.

Subunit / interactions. Interacts with components of the ASC-1 complex TRIP4, ASCC1, ASCC2 and ASCC3. Interact with AHCYL1 and AHCYL2. Interact with YTHDC2.

Subcellular location. Nucleus. Nucleolus. Cytoplasm.

Domain organisation. The regulatory loop blocks the catalytic center by bridging the methyltransferase domain and the C-terminal CCHC-type zinc finger, resulting in an autoinhibitory conformation.

Similarity. Belongs to the ZCCHC4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H5U6-1	1	yes
Q9H5U6-2	2
Q9H5U6-3	3

RefSeq proteins (1): NP_079212* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002052	DNA_methylase_N6_adenine_CS	Conserved_site
IPR010666	Znf_GRF	Domain
IPR039846	ZCCHC4	Family
IPR041370	Mlase_EEF1AKMT1/ZCCHC4	Family

Pfam: PF06839, PF10237

Catalyzed reactions (Rhea), 1 shown:

• adenosine(4220) in 28S rRNA + S-adenosyl-L-methionine = N(6)-methyladenosine(4220) in 28S rRNA + S-adenosyl-L-homocysteine + H(+) (RHEA:58724)

UniProt features (98 total): binding site 29, strand 20, helix 16, turn 10, mutagenesis site 9, compositionally biased region 3, zinc finger region 2, splice variant 2, region of interest 2, sequence variant 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6UCA	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H5U6-F1	83.14	0.64

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 (29): 42; 64; 73; 125; 128; 140; 143; 172–175; 202; 225; 243–244; 276 …

Mutagenesis-validated functional residues (9):

Position	Phenotype
173	abolished rrna methyltransferase activity.
276–279	loss of methyltransferase activity.
276	loss of methyltransferase activity.
340	strongly impaired rrna methyltransferase activity.
341	increased rrna methylation.
342	strongly impaired rrna methyltransferase activity.
343	decreased s-adenosyl-l-methionine-binding.
343	strongly impaired rrna methyltransferase activity.
345	increased rrna methylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): GOBP_RIBOSOME_BIOGENESIS, WANG_CLIM2_TARGETS_UP, MODULE_255, MODULE_317, GOBP_RNA_METHYLATION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_MODIFICATION, MODULE_48, GOBP_RRNA_MODIFICATION, GOBP_METHYLATION, MODULE_95, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, GOBP_RRNA_METHYLATION, GOBP_POSITIVE_REGULATION_OF_TRANSLATION

GO Biological Process (3): rRNA methylation (GO:0031167), positive regulation of translation (GO:0045727), methylation (GO:0032259)

GO Molecular Function (7): nucleic acid binding (GO:0003676), zinc ion binding (GO:0008270), rRNA (adenine-N6-)-methyltransferase activity (GO:0008988), S-adenosyl-L-methionine binding (GO:1904047), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleolus (GO:0005730), cytoplasm (GO:0005737), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cation binding	2
rRNA modification	1
RNA methylation	1
translation	1
regulation of translation	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
metabolic process	1
binding	1
transition metal ion binding	1
N-methyltransferase activity	1
rRNA (adenine) methyltransferase activity	1
sulfur compound binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1503 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZCCHC4	METTL5	Q9NRN9	969
ZCCHC4	LSM12	Q3MHD2	952
ZCCHC4	ZC3H13	Q5T200	946
ZCCHC4	METTL16	Q86W50	946
ZCCHC4	METTL14	Q9HCE5	874
ZCCHC4	VIRMA	Q69YN4	873
ZCCHC4	WTAP	Q15007	861
ZCCHC4	RBM15	Q96T37	820
ZCCHC4	METTL3	Q86U44	788
ZCCHC4	TRMT112	Q9UI30	771
ZCCHC4	CBLL1	Q75N03	630
ZCCHC4	ALKBH5	Q6P6C2	626
ZCCHC4	RBM15B	Q8NDT2	621
ZCCHC4	YTHDC1	Q96MU7	592
ZCCHC4	FTO	Q9C0B1	591

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ZCCHC4	RPS6	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (12): ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Proximity Label-MS), ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Affinity Capture-MS), ZCCHC4 (Affinity Capture-RNA), ZCCHC4 (Proximity Label-MS), ZCCHC4 (Affinity Capture-RNA)

ESM2 similar proteins: A0A1L1SUL6, F1LQY6, O35465, O43379, O75293, O88910, O88954, P0C0T1, P21964, P22339, P41214, P50747, Q13368, Q13572, Q14318, Q16342, Q1HAQ0, Q28955, Q2T9Z1, Q3B7U9, Q3TFD2, Q3TMX7, Q496Y0, Q4AC99, Q5BIM1, Q5E9A5, Q5R812, Q5RA63, Q5SZD4, Q64311, Q6DC64, Q6P5G6, Q6PFY8, Q80YV4, Q8BNV1, Q8BYN3, Q8NFZ0, Q8R1C6, Q8R1T1, Q8TCU6

Diamond homologs: D3ZV31, E1BGQ2, Q66IH9, Q6DCD7, Q8BKW4, Q9H5U6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2549 predictions. Top by Δscore:

Variant	Effect	Δscore
4:25314033:A:AG	acceptor_gain	1.0000
4:25314033:ATTCT:A	acceptor_gain	1.0000
4:25314034:T:G	acceptor_gain	1.0000
4:25314037:T:TA	acceptor_gain	1.0000
4:25314038:G:A	acceptor_gain	1.0000
4:25315314:TCAGT:T	acceptor_loss	1.0000
4:25315316:A:AG	acceptor_gain	1.0000
4:25315317:G:GA	acceptor_gain	1.0000
4:25315317:GT:G	acceptor_gain	1.0000
4:25315317:GTT:G	acceptor_gain	1.0000
4:25315397:AAAG:A	donor_loss	1.0000
4:25315398:AAGGT:A	donor_loss	1.0000
4:25315399:AGGT:A	donor_loss	1.0000
4:25315400:GGTAC:G	donor_loss	1.0000
4:25315401:G:GA	donor_loss	1.0000
4:25315402:T:A	donor_loss	1.0000
4:25333984:TTTCG:T	donor_loss	1.0000
4:25333985:TTCG:T	donor_loss	1.0000
4:25333987:CGG:C	donor_loss	1.0000
4:25333988:GGT:G	donor_loss	1.0000
4:25333989:G:GG	donor_gain	1.0000
4:25333989:GTAGG:G	donor_loss	1.0000
4:25333990:T:G	donor_loss	1.0000
4:25349605:G:GT	donor_gain	1.0000
4:25349609:T:G	donor_gain	1.0000
4:25361858:GGTA:G	acceptor_gain	1.0000
4:25364501:GCCTT:G	donor_gain	1.0000
4:25365127:G:GG	donor_gain	1.0000
4:25365167:G:GG	donor_gain	1.0000
4:25312885:G:GT	donor_gain	0.9900

AlphaMissense

3419 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:25349567:T:C	F279L	0.998
4:25349569:T:A	F279L	0.998
4:25349569:T:G	F279L	0.998
4:25361922:C:A	R359S	0.997
4:25361923:G:C	R359P	0.997
4:25351618:T:A	W314R	0.996
4:25351618:T:C	W314R	0.996
4:25351633:T:C	F319L	0.996
4:25351635:T:A	F319L	0.996
4:25351635:T:G	F319L	0.996
4:25361928:T:C	F361L	0.996
4:25361930:C:A	F361L	0.996
4:25361930:C:G	F361L	0.996
4:25345590:T:A	N243K	0.995
4:25345590:T:G	N243K	0.995
4:25314108:T:C	C64R	0.994
4:25314122:A:C	R68S	0.994
4:25314122:A:T	R68S	0.994
4:25349565:C:A	P278Q	0.994
4:25351630:T:G	Y318D	0.994
4:25361876:T:A	H343Q	0.994
4:25361876:T:G	H343Q	0.994
4:25362230:T:C	C380R	0.994
4:25364501:G:C	K419N	0.994
4:25364501:G:T	K419N	0.994
4:25361865:T:C	Y340H	0.993
4:25361874:C:G	H343D	0.993
4:25361920:T:A	V358E	0.993
4:25361929:T:C	F361S	0.993
4:25314099:T:C	F61L	0.992

dbSNP variants (sampled 300 via entrez): RS1000006328 (4:25321670 G>A), RS1000086427 (4:25343297 T>C), RS1000131705 (4:25328403 C>A), RS1000134812 (4:25314159 G>C,T), RS1000141684 (4:25357019 A>G), RS1000142344 (4:25346989 A>G), RS10001598 (4:25351449 T>C), RS10001797 (4:25323563 A>G), RS1000216876 (4:25332960 G>A,T), RS1000263162 (4:25356752 T>C,G), RS1000349100 (4:25362554 C>G,T), RS1000396824 (4:25340638 C>G), RS10004567 (4:25331229 C>G,T), RS1000505536 (4:25328152 G>A,T), RS1000540433 (4:25331464 C>G,T)

Disease associations

OMIM: gene MIM:611792 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007005_2	Logical memory (immediate recall) in normal cognition	1.000000e-07
GCST010397_101	Gut microbiota (bacterial taxa, rank normal transformation method)	1.000000e-07
GCST010397_94	Gut microbiota (bacterial taxa, rank normal transformation method)	3.000000e-08
GCST012332_61	Multisite chronic pain	1.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0007874	gut microbiome measurement
EFO:0010100	multisite chronic pain

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
deoxynivalenol	increases expression	1
sodium arsenite	increases expression	1
cylindrospermopsin	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
Leflunomide	increases expression	1
Doxorubicin	decreases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TY57	HAP1 ZCCHC4 (-) 1	Cancer cell line	Male
CVCL_TY58	HAP1 ZCCHC4 (-) 2	Cancer cell line	Male
CVCL_TY59	HAP1 ZCCHC4 (-) 3	Cancer cell line	Male
CVCL_TY60	HAP1 ZCCHC4 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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