YEATS4

Summary

YEATS4 (YEATS domain containing 4, HGNC:24859) is a protein-coding gene on chromosome 12q15, encoding YEATS domain-containing protein 4 (O95619). Chromatin reader component of the NuA4 histone acetyltransferase (HAT) complex, a complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. It is a common-essential gene (DepMap: required in 92.3% of cancer cell lines).

The protein encoded by this gene is found in the nucleoli. It has high sequence homology to human MLLT1, and yeast and human MLLT3 proteins. Both MLLT1 and MLLT3 proteins belong to a class of transcription factors, indicating that the encoded protein might also represent a transcription factor. This protein is thought to be required for RNA transcription. This gene has been shown to be amplified in tumors. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 8089 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 15 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 92.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_006530

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24859
Approved symbol	YEATS4
Name	YEATS domain containing 4
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	NuBI-1, GAS41, YAF9
Ensembl gene	ENSG00000127337
Ensembl biotype	protein_coding
OMIM	602116
Entrez	8089

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000247843, ENST00000548020, ENST00000549685, ENST00000552949, ENST00000552955, ENST00000873506, ENST00000923394

RefSeq mRNA: 2 — MANE Select: NM_006530 NM_001300950, NM_006530

CCDS: CCDS73495, CCDS8990

Canonical transcript exons

ENST00000247843 — 7 exons

Exon	Start	End
ENSE00000752251	69370706	69370798
ENSE00000752254	69365790	69365884
ENSE00001259337	69390147	69390870
ENSE00002334661	69359743	69360023
ENSE00003513224	69365633	69365699
ENSE00003564752	69362788	69362907
ENSE00003791663	69370888	69370975

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 95.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.2142 / max 3404.4921, expressed in 1807 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126704	27.7194	1806
126707	0.1902	102
126705	0.1577	52
206789	0.1000	38
126706	0.0469	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.33	gold quality
secondary oocyte	CL:0000655	94.54	gold quality
ventricular zone	UBERON:0003053	92.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.97	gold quality
ganglionic eminence	UBERON:0004023	91.73	gold quality
left testis	UBERON:0004533	89.77	gold quality
right testis	UBERON:0004534	89.73	gold quality
calcaneal tendon	UBERON:0003701	89.63	gold quality
testis	UBERON:0000473	89.18	gold quality
cortical plate	UBERON:0005343	88.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.97	gold quality
embryo	UBERON:0000922	87.68	gold quality
body of pancreas	UBERON:0001150	86.86	gold quality
adrenal tissue	UBERON:0018303	85.90	gold quality
rectum	UBERON:0001052	85.79	gold quality
islet of Langerhans	UBERON:0000006	85.43	gold quality
pancreas	UBERON:0001264	85.40	gold quality
right adrenal gland cortex	UBERON:0035827	84.86	gold quality
bone marrow	UBERON:0002371	84.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.42	gold quality
cerebellar cortex	UBERON:0002129	83.86	gold quality
cerebellar hemisphere	UBERON:0002245	83.85	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.72	gold quality
right adrenal gland	UBERON:0001233	83.57	gold quality
prefrontal cortex	UBERON:0000451	83.54	gold quality
gastrocnemius	UBERON:0001388	83.48	gold quality
left adrenal gland	UBERON:0001234	83.39	gold quality
muscle of leg	UBERON:0001383	83.24	gold quality
left adrenal gland cortex	UBERON:0035825	83.03	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.35

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
TP53	Repression

Upstream regulators (CollecTRI, top): ESR1, MYB, PAX3, SP1, SP3, TFAP2B

miRNA regulators (miRDB)

48 targeting YEATS4, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-153-5P	99.89	73.86	6317
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-3941	99.86	70.54	2735
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-1287-3P	99.63	66.93	492
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-889-3P	99.40	69.76	2103

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 92.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 17)

• Interaction of the transforming acidic coiled-coil 1 (TACC1) protein with ch-TOG and GAS41/NuBI1 suggests multiple TACC1-containing protein complexes in human cells (PMID:11903063)
• GAS41 plays a role in repressing the p53 tumor suppressor pathway during the normal cell cycle by a TIP60-independent mechanism. (PMID:16705155)
• Overexpression of YEATS4 is associated with well-differentiated and dedifferentiated liposarcomas (PMID:18214854)
• The in vivo interaction of GAS41 and endogenous RAP30 and RAP74 was confirmed by co-immunoprecipitation. GAS41 binds to two non-overlapping regions of the C-terminus of RAP30. (PMID:20618999)
• The GAS41-PP2Cbeta complex dephosphorylates p53 at serine 366 and regulates its stability (PMID:21317290)
• Gas41 is able to bind both n-Myc and c-Myc proteins, and that the levels of expression of Gas41 and Myc proteins were similar to each other in such brain tumors as neuroblastomas and glioblastomas. (PMID:22068108)
• Our data confirm previous genome-wide findings at 12q15 and suggest differential YEATS4 expression could underpin rs7297610-associated HCTZ response variability, which may have future implications for guiding thiazide treatment. (PMID:22350108)
• GAS41 amplification results in overexpression and associtated with glioblastoma. (PMID:22619067)
• Findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis (PMID:24170126)
• YEATS4 overexpression is associated with drug resistance of ovarian cancer. (PMID:26307679)
• identified GAS41 as a novel target for endogenous miR-203 and demonstrate an inverse correlation of miR-203 expression with GAS41 in glioma cell lines (PMID:27467502)
• miR-218 sensitized HCT-116/L-OHP cells to L-OHP-induced cell apoptosis via inhibition of cytoprotective autophagy by targeting YEATS4 expression. (PMID:27779719)
• our study demonstrated the oncogenic roles of YEATS4 in the progression of pancreatic cancer by activating beta-catenin/TCF signaling and suggested that YEATS4 might be a promising therapeutic target for pancreatic cancer. (PMID:28445953)
• study identifies GAS41 as a histone acetylation reader that promotes histone H2A.Z deposition in non-small cell lung cancer. (PMID:29437725)
• Cellular and structural studies revealed that GAS41 is a histone lysine succinylation reader owing to a protonated histidine residue located inside the pocket. (PMID:29463709)
• This study determined the crystal structure of the GAS41 YEATS domain with H3K23acK27ac to visualize the molecular basis of diacetylated histone binding. The results suggest a unique binding mode in which full-length GAS41 is a reader of diacetylated histones. (PMID:30071723)
• GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer. (PMID:35503594)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	yeats4	ENSDARG00000045874
mus_musculus	Yeats4	ENSMUSG00000020171
rattus_norvegicus	Yeats4	ENSRNOG00000005689

Protein

Protein identifiers

YEATS domain-containing protein 4 — O95619 (reviewed: O95619)

Alternative names: Glioma-amplified sequence 41, NuMA-binding protein 1

All UniProt accessions (4): O95619, F8VTR4, F8W0J4, F8W1B9

UniProt curated annotations — full annotation on UniProt →

Function. Chromatin reader component of the NuA4 histone acetyltransferase (HAT) complex, a complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. Specifically recognizes and binds acylated histone H3, with a preference for histone H3 diacetylated at ‘Lys-18’ and ‘Lys-27’ (H3K18ac and H3K27ac) or histone H3 diacetylated at ‘Lys-14’ and ‘Lys-27’ (H3K14ac and H3K27ac). Also able to recognize and bind crotonylated histone H3. May also recognize and bind histone H3 succinylated at ‘Lys-122’ (H3K122succ); additional evidences are however required to confirm this result in vivo. Plays a key role in histone variant H2AZ1/H2A.Z deposition into specific chromatin regions: recognizes and binds H3K14ac and H3K27ac on the promoters of actively transcribed genes and recruits NuA4-related complex to deposit H2AZ1/H2A.Z. H2AZ1/H2A.Z deposition is required for maintenance of embryonic stem cell.

Subunit / interactions. Component of numerous complexes with chromatin remodeling and histone acetyltransferase activity. Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6. The NuA4 complex interacts with MYC and the adenovirus E1A protein. Component of a NuA4-related complex which contains EP400, TRRAP/PAF400, SRCAP, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, actin, ACTL6A/BAF53A, VPS72 and YEATS4/GAS41. Interacts with MLLT10/AF10. Also interacts with the SWI/SNF component SMARCB1/BAF47, TACC1 and TACC2, and the nuclear matrix protein NUMA1.

Subcellular location. Nucleus.

Tissue specificity. Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.

Domain organisation. The YEATS domain specifically recognizes and binds acylated histones, with a preference for histone H3 diacetylated at ‘Lys-14’ and ‘Lys-27’ (H3K14ac and H3K27ac).

RefSeq proteins (2): NP_001287879, NP_006521* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005033	YEATS	Family
IPR038704	YEAST_sf	Homologous_superfamily
IPR055129	YEATS_dom	Domain

Pfam: PF03366

UniProt features (27 total): strand 10, helix 4, mutagenesis site 3, region of interest 3, chain 1, domain 1, sequence conflict 1, turn 1, coiled-coil region 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
8IJ0	X-RAY DIFFRACTION	1.52
7EIF	X-RAY DIFFRACTION	1.58
5R68	X-RAY DIFFRACTION	1.64
9X8S	X-RAY DIFFRACTION	1.7
5R69	X-RAY DIFFRACTION	1.83
5VNA	X-RAY DIFFRACTION	2.1
8IIZ	X-RAY DIFFRACTION	2.1
7JFY	X-RAY DIFFRACTION	2.1
5XTZ	X-RAY DIFFRACTION	2.1
8IIY	X-RAY DIFFRACTION	2.15
8I60	X-RAY DIFFRACTION	2.3
9O4Y	X-RAY DIFFRACTION	2.3
5VNB	X-RAY DIFFRACTION	2.4
8DKB	X-RAY DIFFRACTION	2.58
5Y8V	X-RAY DIFFRACTION	2.61
9X8U	X-RAY DIFFRACTION	3
8X15	ELECTRON MICROSCOPY	3.2
8X19	ELECTRON MICROSCOPY	3.2
8X1C	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95619-F1	91.77	0.80

Functional residue map

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

Catalytic / active sites (1): 73 (interacts with diacetylated histone h3)

Post-translational modifications (1): 37

Mutagenesis-validated functional residues (3):

Position	Phenotype
93	impaired binding to histone h3 diacetylated at ’lys-14’ and ’lys-27’ (h3k14ac and h3k27ac), and subsequent deposition of
43	impaired binding to histone h3 succinylated at ’lys-122’ (h3k122succ).
74	impaired binding to histone h3 diacetylated at ’lys-14’ and ’lys-27’ (h3k14ac and h3k27ac), and subsequent deposition of

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones
R-HSA-8866907	Activation of the TFAP2 (AP-2) family of transcription factors

MSigDB gene sets: 171 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, FISCHER_G1_S_CELL_CYCLE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE, NIKOLSKY_BREAST_CANCER_12Q13_Q21_AMPLICON, GOBP_POSITIVE_REGULATION_OF_DNA_REPAIR, GOBP_MITOTIC_CELL_CYCLE, MAGRANGEAS_MULTIPLE_MYELOMA_IGLL_VS_IGLK_UP, MODULE_98

GO Biological Process (11): mitotic cell cycle (GO:0000278), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), regulation of apoptotic process (GO:0042981), positive regulation of DNA-templated transcription (GO:0045893), regulation of cell cycle (GO:0051726), positive regulation of double-strand break repair via homologous recombination (GO:1905168), regulation of double-strand break repair (GO:2000779), chromatin organization (GO:0006325), cytoskeleton organization (GO:0007010)

GO Molecular Function (5): structural constituent of cytoskeleton (GO:0005200), histone binding (GO:0042393), histone H3K18ac reader activity (GO:0140044), histone H3K27ac reader activity (GO:0140119), protein binding (GO:0005515)

GO Cellular Component (6): nucleosome (GO:0000786), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear matrix (GO:0016363), nuclear membrane (GO:0031965), NuA4 histone acetyltransferase complex (GO:0035267)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell cycle	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
histone H3 reader activity	2
nuclear lumen	2
cellular anatomical structure	2
mitotic nuclear division	1
chromatin organization	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
apoptotic process	1
regulation of programmed cell death	1
positive regulation of RNA biosynthetic process	1
regulation of cellular process	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
positive regulation of DNA recombination	1
positive regulation of double-strand break repair	1
regulation of DNA repair	1
double-strand break repair	1
cellular component organization	1
organelle organization	1
structural molecule activity	1
cytoskeleton	1
cytoskeleton organization	1
protein binding	1
binding	1
chromatin	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nucleus	1
nuclear envelope	1
organelle membrane	1
H4/H2A histone acetyltransferase complex	1

Protein interactions and networks

STRING

2274 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YEATS4	DMAP1	Q9NPF5	994
YEATS4	VPS72	Q15906	942
YEATS4	MEAF6	Q9HAF1	942
YEATS4	RUVBL2	Q9Y230	941
YEATS4	CFDP1	Q9UEE9	928
YEATS4	MORF4L1	Q9UBU8	927
YEATS4	MRGBP	Q9NV56	920
YEATS4	BRD8	Q9H0E9	908
YEATS4	RUVBL1	P82276	903
YEATS4	KAT5	Q92993	894
YEATS4	SRCAP	Q6ZRS2	857
YEATS4	EP400	Q96L91	845
YEATS4	ING3	Q9NXR8	845
YEATS4	MLLT10	P55197	816
YEATS4	H2AZ1	P0C0S5	813

IntAct

191 interactions, top by confidence:

A	B	Type	Score
RUVBL1	ZNHIT1	psi-mi:“MI:0914”(association)	0.860
MRGBP	YEATS4	psi-mi:“MI:0914”(association)	0.840
RUVBL2	ZNHIT1	psi-mi:“MI:0914”(association)	0.810
YEATS4	ZNHIT1	psi-mi:“MI:0914”(association)	0.790
ZNHIT1	YEATS4	psi-mi:“MI:0914”(association)	0.790
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
MED23	MED19	psi-mi:“MI:2364”(proximity)	0.770
MBTD1	YEATS4	psi-mi:“MI:0914”(association)	0.730
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
MORF4L1	SIN3B	psi-mi:“MI:0914”(association)	0.730
ACTL6A	ZNHIT1	psi-mi:“MI:0914”(association)	0.720
VPS72	ZNHIT1	psi-mi:“MI:0914”(association)	0.690
ANKK1	YEATS4	psi-mi:“MI:0915”(physical association)	0.670
YEATS4	ANKK1	psi-mi:“MI:0915”(physical association)	0.670
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640

BioGRID (351): YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS), EP400 (Affinity Capture-MS), FUS (Affinity Capture-MS), MEAF6 (Affinity Capture-MS), EPC1 (Affinity Capture-MS), EPC2 (Affinity Capture-MS), SRCAP (Affinity Capture-MS)

ESM2 similar proteins: D3ZRP6, D4A055, F1QH17, O22715, O60493, O70492, O70493, O95619, P0CR61, P48454, P48455, Q0G819, Q15691, Q1RMH8, Q1RMS5, Q27889, Q28E02, Q2U4K2, Q3SYW1, Q3ZBD9, Q4I1H6, Q4WWS3, Q5R5V1, Q5R752, Q5R7Z5, Q5U211, Q5XH73, Q5ZKU1, Q5ZLC7, Q60EW9, Q61166, Q66HR2, Q66T82, Q68FK8, Q6AXU9, Q6C2S9, Q6IR85, Q6P848, Q6V291, Q76EZ2

Diamond homologs: A2AM29, F4IPK2, O94436, O95619, P35189, P42568, P53930, Q03111, Q4I7S1, Q4PFI5, Q4WPM8, Q59LC9, Q5BC71, Q6CIV8, Q6FXM4, Q755P0, Q9CR11, Q9FH40, P0CM08, P0CM09, Q10319, Q6CF24, Q7RZK7, Q99314, Q3TUF7, Q9ULM3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
YEATS4	“form complex”	“NuA4 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 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
HATs acetylate histones	22	17.1×	9e-19
DNA Damage Recognition in GG-NER	5	14.0×	2e-03
Chromatin organization	14	11.2×	6e-09
Deposition of new CENPA-containing nucleosomes at the centromere	7	10.9×	4e-04
Maturation of DENV proteins	5	10.4×	5e-03
Chromatin modifying enzymes	14	9.9×	2e-08
DNA Damage/Telomere Stress Induced Senescence	6	9.6×	2e-03
Formation of the beta-catenin:TCF transactivating complex	8	9.4×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of double-strand break repair	18	72.6×	5e-28
positive regulation of double-strand break repair via homologous recombination	18	47.9×	7e-24
positive regulation of telomere maintenance in response to DNA damage	5	39.0×	1e-05
regulation of DNA strand elongation	5	36.6×	1e-05
regulation of chromosome organization	5	32.5×	2e-05
regulation of DNA replication	9	22.9×	2e-08
positive regulation of DNA repair	7	17.4×	1e-05
regulation of insulin secretion	5	13.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1242 predictions. Top by Δscore:

Variant	Effect	Δscore
12:69360015:A:T	donor_gain	1.0000
12:69360020:AAAGG:A	donor_loss	1.0000
12:69360021:AAGGT:A	donor_loss	1.0000
12:69360023:GGT:G	donor_loss	1.0000
12:69360024:G:GA	donor_loss	1.0000
12:69362783:TTTA:T	acceptor_loss	1.0000
12:69362786:A:AG	acceptor_gain	1.0000
12:69362786:A:AT	acceptor_loss	1.0000
12:69362786:AG:A	acceptor_gain	1.0000
12:69362786:AGGGT:A	acceptor_gain	1.0000
12:69362787:G:A	acceptor_gain	1.0000
12:69362787:G:GC	acceptor_loss	1.0000
12:69362787:G:GG	acceptor_gain	1.0000
12:69362787:GGGT:G	acceptor_gain	1.0000
12:69362787:GGGTG:G	acceptor_gain	1.0000
12:69362905:GAG:G	donor_gain	1.0000
12:69362905:GAGGT:G	donor_loss	1.0000
12:69362906:AGGT:A	donor_loss	1.0000
12:69362908:G:GG	donor_gain	1.0000
12:69365788:A:AG	acceptor_gain	1.0000
12:69365789:G:GG	acceptor_gain	1.0000
12:69365789:GTT:G	acceptor_gain	1.0000
12:69365880:GACCT:G	donor_gain	1.0000
12:69365882:CCT:C	donor_gain	1.0000
12:69365885:G:GG	donor_gain	1.0000
12:69370702:A:AG	acceptor_gain	1.0000
12:69370703:C:G	acceptor_gain	1.0000
12:69370704:A:AG	acceptor_gain	1.0000
12:69370704:A:T	acceptor_loss	1.0000
12:69370704:AG:A	acceptor_gain	1.0000

AlphaMissense

1501 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:69360016:G:C	R15T	1.000
12:69360017:A:C	R15S	1.000
12:69360017:A:T	R15S	1.000
12:69362810:T:A	I25K	1.000
12:69362813:T:A	V26D	1.000
12:69362818:G:C	G28R	1.000
12:69362818:G:T	G28C	1.000
12:69362819:G:A	G28D	1.000
12:69362819:G:T	G28V	1.000
12:69362823:T:A	N29K	1.000
12:69362823:T:G	N29K	1.000
12:69362827:G:C	A31P	1.000
12:69362828:C:A	A31D	1.000
12:69362850:A:C	R38S	1.000
12:69362850:A:T	R38S	1.000
12:69362857:G:C	D41H	1.000
12:69362863:C:G	H43D	1.000
12:69362867:C:T	T44I	1.000
12:69362869:C:A	H45N	1.000
12:69362869:C:G	H45D	1.000
12:69362870:A:C	H45P	1.000
12:69362870:A:G	H45R	1.000
12:69362871:T:A	H45Q	1.000
12:69362871:T:G	H45Q	1.000
12:69362875:T:A	W47R	1.000
12:69362875:T:C	W47R	1.000
12:69362876:G:C	W47S	1.000
12:69362876:G:T	W47L	1.000
12:69362877:G:C	W47C	1.000
12:69362877:G:T	W47C	1.000

dbSNP variants (sampled 300 via entrez): RS1000028479 (12:69424133 A>C), RS1000043088 (12:69367220 A>G), RS1000091378 (12:69398087 G>A), RS1000101451 (12:69423862 G>A), RS1000130948 (12:69448817 C>A), RS1000146585 (12:69379797 C>T), RS1000162050 (12:69448499 G>A), RS1000188666 (12:69393590 A>G), RS1000194429 (12:69395312 G>A,C), RS1000211282 (12:69453891 C>A,G), RS1000222657 (12:69361050 T>A,C), RS1000226263 (12:69449307 T>G), RS1000249939 (12:69392562 A>G), RS1000282497 (12:69461142 G>A), RS1000288661 (12:69399329 T>A)

Disease associations

OMIM: gene MIM:602116 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000175_26	Height	3.000000e-06
GCST000208_1	Response to diuretic therapy	3.000000e-07
GCST005836_1	Response to SSRI in MDD or conscientiousness	4.000000e-08
GCST007061_1	Response to antidepressants (symptom remission)	4.000000e-06
GCST007424_1	Complete remission in asthma	5.000000e-07
GCST008839_58	Height	6.000000e-18
GCST009391_1858	Metabolite levels	4.000000e-06
GCST009391_1878	Metabolite levels	2.000000e-06
GCST010653_21	Thyroid stimulating hormone levels	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0007912	conscientiousness measurement
EFO:0009785	remission
EFO:0010410	triacylglycerol 50:3 measurement
EFO:0010414	triacylglycerol 52:2 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296266 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7297610	Efficacy	3	hydrochlorothiazide	Essential hypertension;Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7297610	YEATS4	3	4.50	1	hydrochlorothiazide

ChEMBL bioactivities

28 potent at pChembl≥5 of 29 total, top 28 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.68	Ki	21	nM	CHEMBL5397585
7.52	Kd	30	nM	CHEMBL5439842
7.48	Ki	33	nM	CHEMBL5414722
7.48	Ki	33	nM	CHEMBL5428051
7.43	Ki	37	nM	CHEMBL5439842
7.37	Ki	43	nM	CHEMBL5432565
7.35	Kd	45	nM	CHEMBL5434894
7.28	Kd	53	nM	CHEMBL5397585
7.28	Kd	52.7	nM	CHEMBL5428051
7.25	Ki	56	nM	CHEMBL5439506
7.24	Ki	57	nM	CHEMBL5426169
7.23	Ki	59	nM	CHEMBL5434894
7.20	Ki	63	nM	CHEMBL5411016
7.16	Ki	69	nM	CHEMBL5432083
7.10	Kd	80	nM	CHEMBL5411016
7.02	IC50	96	nM	CHEMBL5409682
6.99	Kd	103	nM	CHEMBL5397585
6.85	Ki	141	nM	CHEMBL5429949
6.77	IC50	170	nM	CHEMBL5428051
6.70	IC50	200	nM	CHEMBL5397585
6.55	Ki	284	nM	CHEMBL5435884
6.54	IC50	290	nM	CHEMBL5411016
6.53	Kd	297	nM	CHEMBL5434894
6.52	IC50	300	nM	CHEMBL5439842
6.47	Kd	340	nM	CHEMBL5428051
6.28	Kd	530	nM	CHEMBL5411016
6.27	Ki	540	nM	CHEMBL5439514
6.14	IC50	730	nM	CHEMBL5434894

PubChem BioAssay actives

28 with measured affinity, of 63 total; 14 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
N-ethyl-3-[1-[(2-hydroxy-2-adamantyl)methyl]piperidin-4-yl]-2-methylpyrazolo[1,5-a]pyridine-6-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0210	uM
N-ethyl-3-[(3R,4S)-1-[(4-hydroxyoxan-4-yl)methyl]-3-methylpiperidin-4-yl]-2-methylpyrazolo[1,5-a]pyridine-6-carboxamide	1964949: Binding affinity to YEATS4 (unknown origin) assessed as dissociation constant by isothermal calorimetric analysis	kd	0.0300	uM
N-ethyl-3-[(3R,4S)-1-[(1-hydroxycyclohexyl)methyl]-3-methylpiperidin-4-yl]-2-methylpyrazolo[1,5-a]pyridine-6-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0330	uM
N-ethyl-1-[(3S,4S)-1-[(1-hydroxycyclohexyl)methyl]-3-methylpiperidin-4-yl]-2-(1-methyl-2-oxo-3-pyridinyl)benzimidazole-5-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0330	uM
N-(cyclopropylmethyl)-3-[(3R,4S)-1-[(4-hydroxyoxan-4-yl)methyl]-3-methylpiperidin-4-yl]-2-methylpyrazolo[1,5-a]pyridine-6-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0430	uM
2-(difluoromethyl)-N-ethyl-1-[(3S,4S)-1-[(1-hydroxycyclohexyl)methyl]-3-methylpiperidin-4-yl]benzimidazole-5-carboxamide	1964949: Binding affinity to YEATS4 (unknown origin) assessed as dissociation constant by isothermal calorimetric analysis	kd	0.0450	uM
N-ethyl-3-[1-[(1-hydroxycyclohexyl)methyl]piperidin-4-yl]-2-methylpyrazolo[1,5-a]pyridine-6-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0560	uM
N-(cyclopropylmethyl)-3-[(3R,4S)-1-[(4-methoxyoxan-4-yl)methyl]-3-methylpiperidin-4-yl]-2-methylpyrazolo[1,5-a]pyridine-6-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0570	uM
N-ethyl-1-[(3S,4S)-1-[(1-hydroxycyclohexyl)methyl]-3-methylpiperidin-4-yl]-2-methylbenzimidazole-5-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0630	uM
N-ethyl-3-[1-[(1-hydroxycyclohexyl)methyl]piperidin-4-yl]-2-(1-methyl-2-oxo-3-pyridinyl)pyrazolo[1,5-a]pyridine-6-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.0690	uM
(2S,4R)-N-[5-[3-(1,3-benzothiazol-2-yl)azetidine-1-carbonyl]thiophen-2-yl]-4-[5-[(3R,5S)-5-[[5-[3-(1,3-benzothiazol-2-yl)azetidine-1-carbonyl]thiophen-2-yl]carbamoyl]pyrrolidin-3-yl]oxypentoxy]pyrrolidine-2-carboxamide	2026852: Inhibition of human N-terminal GST tagged GAS41 (1 to 148 residues) incubated for 1 hr by fluorescence polarization assay	ic50	0.0960	uM
N-ethyl-1-[1-[(1-hydroxycyclohexyl)methyl]piperidin-4-yl]-2-methylbenzimidazole-5-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.1410	uM
N-ethyl-1-[1-[(1-hydroxycyclohexyl)methyl]piperidin-4-yl]-2-oxo-3H-benzimidazole-5-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.2840	uM
1-[1-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]piperidin-4-yl]-N-ethyl-2-oxo-3H-benzimidazole-5-carboxamide	1964934: Binding affinity to human his-tagged recombinant YEATS4 expressed in Escherichia coli assessed as inhibition constant using biotin tagged lysine 27-crotonylated histone H3 peptide as substrate preincubated for 20 mins followed by substrate addition measured after 30 mins by FRET analysis	ki	0.5400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression	3
Tretinoin	decreases expression	2
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ketoconazole	increases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Lactic Acid	decreases expression	1
Vitamin K 3	affects expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

26 unique, capped per target: 26 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4810342	Binding	Inhibition of human His-GAS41 YEATS domain and biotinylated H3K27ac peptide interaction by AlphaScreen assay	Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain. — J Med Chem

Clinical trials (associated diseases)

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