YTHDF2

Summary

YTHDF2 (YTH N6-methyladenosine RNA binding protein F2, HGNC:31675) is a protein-coding gene on chromosome 1p35.3, encoding YTH domain-containing family protein 2 (Q9Y5A9). Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability. It is a selective cancer dependency (DepMap: 27.6% of cell lines).

This gene encodes a member of the YTH (YT521-B homology) superfamily containing YTH domain. The YTH domain is typical for the eukaryotes and is particularly abundant in plants. The YTH domain is usually located in the middle of the protein sequence and may function in binding to RNA. In addition to a YTH domain, this protein has a proline rich region which may be involved in signal transduction. An Alu-rich domain has been identified in one of the introns of this gene, which is thought to be associated with human longevity. In addition, reciprocal translocations between this gene and the Runx1 (AML1) gene on chromosome 21 has been observed in patients with acute myeloid leukemia. This gene was initially mapped to chromosome 14, which was later turned out to be a pseudogene. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.

Source: NCBI Gene 51441 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 57 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 27.6% of screened cell lines
• MANE Select transcript: NM_016258

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31675
Approved symbol	YTHDF2
Name	YTH N6-methyladenosine RNA binding protein F2
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Aliases	HGRG8, NY-REN-2, CAHL
Ensembl gene	ENSG00000198492
Ensembl biotype	protein_coding
OMIM	610640
Entrez	51441

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000373812, ENST00000468863, ENST00000474884, ENST00000475796, ENST00000476976, ENST00000478283, ENST00000496288, ENST00000541996, ENST00000542507, ENST00000856190

RefSeq mRNA: 3 — MANE Select: NM_016258 NM_001172828, NM_001173128, NM_016258

CCDS: CCDS41296, CCDS53287

Canonical transcript exons

ENST00000373812 — 5 exons

Exon	Start	End
ENSE00001065066	28768929	28769775
ENSE00001546244	28736940	28737147
ENSE00003490348	28742403	28743986
ENSE00003524053	28737658	28737682
ENSE00003547472	28738259	28738338

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 96.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.9199 / max 405.7555, expressed in 1826 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1833	54.4247	1823
1834	8.9862	1780
1832	3.8899	1418
1836	1.1145	570
1835	1.0001	605
1829	0.8750	228
1837	0.8722	365
1831	0.4400	129
1838	0.1588	72
1830	0.1060	47

Top tissues by expression

138 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	96.56	gold quality
cortical plate	UBERON:0005343	96.08	gold quality
cerebellar vermis	UBERON:0004720	95.65	gold quality
quadriceps femoris	UBERON:0001377	95.55	gold quality
ganglionic eminence	UBERON:0004023	95.42	gold quality
islet of Langerhans	UBERON:0000006	94.87	gold quality
stromal cell of endometrium	CL:0002255	94.51	gold quality
bone marrow cell	CL:0002092	94.13	gold quality
bone marrow	UBERON:0002371	94.05	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.84	gold quality
skin of abdomen	UBERON:0001416	93.54	gold quality
ventricular zone	UBERON:0003053	93.42	gold quality
endometrium	UBERON:0001295	93.31	gold quality
zone of skin	UBERON:0000014	93.23	gold quality
smooth muscle tissue	UBERON:0001135	93.21	gold quality
tonsil	UBERON:0002372	93.11	gold quality
skin of leg	UBERON:0001511	92.98	gold quality
right adrenal gland cortex	UBERON:0035827	92.98	gold quality
rectum	UBERON:0001052	92.89	gold quality
placenta	UBERON:0001987	92.80	gold quality
esophagus mucosa	UBERON:0002469	92.78	gold quality
right adrenal gland	UBERON:0001233	92.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.58	gold quality
gastrocnemius	UBERON:0001388	92.57	gold quality
left adrenal gland	UBERON:0001234	92.54	gold quality
lymph node	UBERON:0000029	92.51	gold quality
adrenal tissue	UBERON:0018303	92.34	gold quality
adrenal gland	UBERON:0002369	92.28	gold quality
muscle of leg	UBERON:0001383	92.20	gold quality
left adrenal gland cortex	UBERON:0035825	92.20	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7052	no	546.41
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

124 targeting YTHDF2, 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-4668-3P	100.00	68.74	2635
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4753-3P	99.90	71.03	3786
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 27.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• PMID:10508479 reported that AF155095 (clone REN-2) may be involved in signal transduction and the gene is on chromosome 14. It turns out that it is the pseudogene, not the real gene, is located on chromosome 14. (PMID:10508479)
• YTHDF2 messenger RNA resulted to be mainly expressed in testis and placenta. The data suggest a possible role of this locus in human longevity. (PMID:16799135)
• m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ protein to regulate mRNA degradation (PMID:24284625)
• The study presents the structure of YTH-YTHDF2 in complex with an N6-methyladenosine mononucleotide. (PMID:25412658)
• The basic residues K416 and R527 on the surface of the YTH domain of YTHDF2 are involved in binding to the RNA backbone, and residues W432 and W486 within the hydrophobic pocket contribute to the specific recognition of N6-methyladenosine. (PMID:25412661)
• binding affinities of the YTH domains of three human proteins and yeast YTH domain protein Pho92 (PMID:26318451)
• The authors found that the overexpression of YTHDF proteins in cells inhibited HIV-1 infection mainly by decreasing HIV-1 reverse transcription, while knockdown of YTHDF1-3 in cells had the opposite effects. Moreover, silencing the N(6)-methyladenosine writers decreased HIV-1 Gag protein expression in virus-producing cells, while silencing the N(6)-methyladenosine erasers increased Gag expression. (PMID:27371828)
• YTHDF2 recruits the CCR4-NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m6A-containing RNAs by CAF1 and CCR4. (PMID:27558897)
• miR-145 modulates N(6)-methyladenosine levels by targeting the 3’-UTR of YTHDF2 mRNA in hepatocellular carcinoma cells (PMID:28104805)
• YTHDF2 knockdown significantly increases the total YAP expression, but inhibits TGF-beta/Smad signaling, indicating that YTHDF2 regulates EMT probably via YAP signaling. (PMID:29135329)
• apoptosis ratio of YTHDF2-shRNA-expressing MGC-803 cells was significantly higher compared with the control groups (PMID:29382422)
• YTHDF2 may act as a tumor suppressor to repress cell proliferation and growth by destabilizing the EGFR mRNA in hepatocellular carcinoma cells. (PMID:30423408)
• We also find that a subset of m(6)A-containing circular RNAs associates with YTHDF2 in an HRSP12-dependent manner and is selectively downregulated by RNase P/MRP. (PMID:30930054)
• Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. (PMID:31031138)
• YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation. (PMID:31504235)
• Binding to m(6)A RNA promotes YTHDF2-mediated phase separation. (PMID:31642031)
• Our results have characterized the m(6)A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular ‘rheostat’ in epitranscriptome and cancer progression. (PMID:31735169)
• YTHDF2 Binds to 5-Methylcytosine in RNA and Modulates the Maturation of Ribosomal RNA. (PMID:31815440)
• Molecular Mechanisms Driving mRNA Degradation by m(6)A Modification. (PMID:31964509)
• m(6) A RNA methylation regulators contribute to malignant progression in rectal cancer. (PMID:32043594)
• METTL3/YTHDF2 m(6) A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer. (PMID:32126149)
• Results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in induced pluripotent stem cells and facilitate their rapid and coordinated up-regulation during neural induction. (PMID:32169943)
• YTHDF2 stability is maintained by CDK1.YTHDF2 promotes mRNA decay during cell cycle.Proteolysis pathway of YTHDF2. (PMID:32267835)
• YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. (PMID:32366907)
• [Knockdown of YTH N(6)-methyladenosine RNA binding protein 2 (YTHDF2) inhibits cell proliferation and promotes apoptosis in cervical cancer cells]. (PMID:32389174)
• The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus. (PMID:32583611)
• Decreased ALKBH5, FTO, and YTHDF2 in Peripheral Blood Are as Risk Factors for Rheumatoid Arthritis. (PMID:32884942)
• YTHDF2/3 Are Required for Somatic Reprogramming through Different RNA Deadenylation Pathways. (PMID:32905781)
• YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells. (PMID:32948220)
• YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. (PMID:33121495)
• METTL3/YTHDF2 m6A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5. (PMID:33411363)
• EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. (PMID:33420027)
• SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs. (PMID:33577677)
• FTO regulates myoblast proliferation by controlling CCND1 expression in an m(6)A-YTHDF2-dependent manner. (PMID:33651996)
• FBW7 suppresses ovarian cancer development by targeting the N(6)-methyladenosine binding protein YTHDF2. (PMID:33658012)
• N-methyladenosine reader YTHDF2-mediated long noncoding RNA FENDRR degradation promotes cell proliferation in endometrioid endometrial carcinoma. (PMID:33692441)
• Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. (PMID:33726814)
• YTHDF2 is a potential target of AML1/ETO-HIF1alpha loop-mediated cell proliferation in t(8;21) AML. (PMID:33958724)
• RNA m(6)A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/beta-catenin signaling. (PMID:33980824)
• PBRM1 Cooperates with YTHDF2 to Control HIF-1alpha Protein Translation. (PMID:34200988)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ythdf2	ENSDARG00000014498
mus_musculus	Ythdf2	ENSMUSG00000040025
rattus_norvegicus	Ythdf2	ENSRNOG00000010892
drosophila_melanogaster	Ythdf	FBGN0039261

Paralogs (3): YTHDC1 (ENSG00000083896), YTHDF1 (ENSG00000149658), YTHDF3 (ENSG00000185728)

Protein

Protein identifiers

YTH domain-containing family protein 2 — Q9Y5A9 (reviewed: Q9Y5A9)

Alternative names: CLL-associated antigen KW-14, High-glucose-regulated protein 8, Renal carcinoma antigen NY-REN-2

All UniProt accessions (3): Q9Y5A9, S4R3J8, S4R3V3

UniProt curated annotations — full annotation on UniProt →

Function. Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability. M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing. Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT and ribonuclease P/MRP complexes, depending on the context. The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation. M6A-containing mRNAs containing a binding site for RIDA/HRSP12 (5’-GGUUC-3’) are preferentially degraded by endoribonucleolytic cleavage: cooperative binding of RIDA/HRSP12 and YTHDF2 to transcripts leads to recruitment of the ribonuclease P/MRP complex. Other m6A-containing mRNAs undergo deadenylation via direct interaction between YTHDF2 and CNOT1, leading to recruitment of the CCR4-NOT and subsequent deadenylation of m6A-containing mRNAs. Required maternally to regulate oocyte maturation: probably acts by binding to m6A-containing mRNAs, thereby regulating maternal transcript dosage during oocyte maturation, which is essential for the competence of oocytes to sustain early zygotic development. Also required during spermatogenesis: regulates spermagonial adhesion by promoting degradation of m6A-containing transcripts coding for matrix metallopeptidases. Also involved in hematopoietic stem cells specification by binding to m6A-containing mRNAs, leading to promote their degradation. Also acts as a regulator of neural development by promoting m6A-dependent degradation of neural development-related mRNA targets. Inhibits neural specification of induced pluripotent stem cells by binding to methylated neural-specific mRNAs and promoting their degradation, thereby restraining neural differentiation. Regulates circadian regulation of hepatic lipid metabolism: acts by promoting m6A-dependent degradation of PPARA transcripts. Regulates the innate immune response to infection by inhibiting the type I interferon response: acts by binding to m6A-containing IFNB transcripts and promoting their degradation. May also act as a promoter of cap-independent mRNA translation following heat shock stress: upon stress, relocalizes to the nucleus and specifically binds mRNAs with some m6A methylation mark at their 5’-UTR, protecting demethylation of mRNAs by FTO, thereby promoting cap-independent mRNA translation. Regulates mitotic entry by promoting the phase-specific m6A-dependent degradation of WEE1 transcripts. Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules. May also recognize and bind RNAs modified by C5-methylcytosine (m5C) and act as a regulator of rRNA processing. (Microbial infection) Promotes viral gene expression and replication of polyomavirus SV40: acts by binding to N6-methyladenosine (m6A)-containing viral RNAs. (Microbial infection) Promotes viral gene expression and virion production of kaposis sarcoma-associated herpesvirus (KSHV) at some stage of the KSHV life cycle (in iSLK.219 and iSLK.BAC16 cells). Acts by binding to N6-methyladenosine (m6A)-containing viral RNAs.

Subunit / interactions. Interacts with CNOT1; interaction is direct and promotes recruitment of the CCR4-NOT complex. Interacts with YTHDF3. Interacts with RIDA/HRSP12; interaction leads to recruitment of the ribonuclease P/MRP complex.

Subcellular location. Cytoplasm. Cytosol. P-body. Stress granule. Nucleus.

Tissue specificity. Highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation.

Post-translational modifications. Ubiquitinated by the SCF(SKP2) complex, leading to its degradation.

Domain organisation. The disordered regions have the ability to interact with each other and to ‘phase separate’ into liquid droplets within the cytosol following binding to mRNAs containing multiple m6A-modified residues. This leads to the partition of m6A-containing mRNAs into membraneless compartments, where mRNAs may be stored, degraded or used to transport mRNAs to dendritic arbors in neurons.

Induction. Following heat shock stress.

Similarity. Belongs to the YTHDF family. YTHDF2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5A9-1	1	yes
Q9Y5A9-2	2

RefSeq proteins (3): NP_001166299, NP_001166599, NP_057342* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007275	YTH_domain	Domain
IPR045168	YTH_prot	Family

Pfam: PF04146

UniProt features (50 total): modified residue 9, mutagenesis site 7, strand 7, binding site 6, helix 5, compositionally biased region 4, region of interest 4, sequence variant 2, turn 2, initiator methionine 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
7R5L	X-RAY DIFFRACTION	1.7
7Z5M	X-RAY DIFFRACTION	1.7
9QFL	X-RAY DIFFRACTION	1.7
7R5W	X-RAY DIFFRACTION	1.75
7YX6	X-RAY DIFFRACTION	1.8
7Z7B	X-RAY DIFFRACTION	1.8
7Z54	X-RAY DIFFRACTION	1.82
7Z4U	X-RAY DIFFRACTION	1.83
7YXE	X-RAY DIFFRACTION	1.85
9QEL	X-RAY DIFFRACTION	1.86
7Z26	X-RAY DIFFRACTION	1.9
7Z8W	X-RAY DIFFRACTION	1.9
7Z92	X-RAY DIFFRACTION	1.91
9QFI	X-RAY DIFFRACTION	1.91
7YWB	X-RAY DIFFRACTION	1.92
7Z7F	X-RAY DIFFRACTION	1.95
7Z8X	X-RAY DIFFRACTION	1.96
7Z8P	X-RAY DIFFRACTION	1.97
7Z93	X-RAY DIFFRACTION	1.97
9QEO	X-RAY DIFFRACTION	1.98
7R5F	X-RAY DIFFRACTION	2
7ZG4	X-RAY DIFFRACTION	2.01
4RDN	X-RAY DIFFRACTION	2.1
7BIK	X-RAY DIFFRACTION	2.1
4WQN	X-RAY DIFFRACTION	2.12
4RDO	X-RAY DIFFRACTION	2.15
7A1V	X-RAY DIFFRACTION	2.2
9QEM	X-RAY DIFFRACTION	2.26
9QIU	X-RAY DIFFRACTION	2.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5A9-F1	61.14	0.31

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 (6): 416–418; 422; 432–433; 462; 486; 491

Post-translational modifications (9): 2, 2, 4, 5, 22, 39, 196, 359, 394

Mutagenesis-validated functional residues (7):

Position	Phenotype
411	slightly decreased binding to rnas.
416	decreased binding to rnas.
432	reduced binding to n6-methyladenosine (m6a)-containing rnas. reduced ability to undergo liquid-liquid phase separation.
441	slightly decreased binding to rnas.
486	reduced binding to n6-methyladenosine (m6a)-containing rnas. reduced ability to undergo liquid-liquid phase separation;
491	reduced binding to n6-methyladenosine (m6a)-containing rnas.
527	decreased binding to rnas.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 313 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, RORA1_01, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_STEM_CELL_DIFFERENTIATION, GOBP_OOGENESIS, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (27): oocyte maturation (GO:0001556), mRNA catabolic process (GO:0006402), humoral immune response (GO:0006959), gamete generation (GO:0007276), spermatogonial cell division (GO:0007284), regulation of cell adhesion (GO:0030155), stress granule assembly (GO:0034063), regulation of mRNA stability (GO:0043488), innate immune response (GO:0045087), negative regulation of Notch signaling pathway (GO:0045746), embryonic morphogenesis (GO:0048598), regulation of neurogenesis (GO:0050767), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), mRNA destabilization (GO:0061157), organelle assembly (GO:0070925), hematopoietic stem cell proliferation (GO:0071425), endothelial to hematopoietic transition (GO:0098508), regulation of hematopoietic stem cell differentiation (GO:1902036), regulation of meiotic cell cycle process involved in oocyte maturation (GO:1903538), positive regulation of cap-independent translational initiation (GO:1903679), regulation of rRNA processing (GO:2000232), negative regulation of stem cell differentiation (GO:2000737), immune system process (GO:0002376), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), oogenesis (GO:0048477), cell division (GO:0051301)

GO Molecular Function (5): RNA binding (GO:0003723), mRNA binding (GO:0003729), C5-methylcytidine-containing RNA reader activity (GO:0062153), N6-methyladenosine-containing RNA reader activity (GO:1990247), protein binding (GO:0005515)

GO Cellular Component (7): P-body (GO:0000932), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), centriolar satellite (GO:0034451), cytoplasmic ribonucleoprotein granule (GO:0036464)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA binding	3
cellular anatomical structure	3
negative regulation of gene expression	2
immune response	2
protein-RNA adaptor activity	2
cytoplasmic ribonucleoprotein granule	2
cytoplasm	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
RNA catabolic process	1
mRNA metabolic process	1
sexual reproduction	1
multicellular organismal reproductive process	1
spermatogenesis	1
cell division	1
cell adhesion	1
regulation of cellular process	1
membraneless organelle assembly	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
defense response to symbiont	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
anatomical structure morphogenesis	1
embryo development	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
regulation of mRNA stability	1
RNA destabilization	1
positive regulation of mRNA catabolic process	1
organelle organization	1
cellular component assembly	1
hemopoiesis	1

Protein interactions and networks

STRING

2186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YTHDF2	RIDA	P52758	989
YTHDF2	CNOT1	A5YKK6	980
YTHDF2	YTHDF3	Q7Z739	971
YTHDF2	METTL14	Q9HCE5	945
YTHDF2	METTL3	Q86U44	939
YTHDF2	WTAP	Q15007	907
YTHDF2	ALKBH5	Q6P6C2	904
YTHDF2	VIRMA	Q69YN4	892
YTHDF2	FTO	Q9C0B1	890
YTHDF2	FMR1	Q06787	867
YTHDF2	HNRNPC	P07910	866
YTHDF2	HNRNPA2B1	P22626	855
YTHDF2	ZC3H13	Q5T200	854
YTHDF2	IGF2BP1	Q9NZI8	853
YTHDF2	RBM15	Q96T37	853

IntAct

136 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
KIF1C	KIF1B	psi-mi:“MI:2364”(proximity)	0.480
SAMD4A	INPPL1	psi-mi:“MI:2364”(proximity)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
ENG	YTHDF2	psi-mi:“MI:0407”(direct interaction)	0.440
IRAK2	YTHDF2	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
Hnrnpf	MATR3	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
NBEAL2	HAX1	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
DICER1	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
STK38L		psi-mi:“MI:0914”(association)	0.350

BioGRID (630): YTHDF2 (Affinity Capture-MS), YTHDF2 (Affinity Capture-MS), YTHDF2 (Affinity Capture-MS), AGL (Co-fractionation), HMBS (Co-fractionation), YTHDF2 (Co-fractionation), YTHDF2 (Co-fractionation), YTHDF2 (Co-fractionation), YTHDF2 (Co-fractionation), YTHDF2 (Co-fractionation), YTHDF2 (Affinity Capture-MS), YTHDF2 (Proximity Label-MS), YTHDF2 (Proximity Label-MS), YTHDF2 (Proximity Label-MS), YTHDF2 (Affinity Capture-MS)

ESM2 similar proteins: A5D7P8, A6QLK2, F1LQ48, O55047, O95628, P25916, P35226, P59326, P97855, Q08CW1, Q0VCY1, Q0VCZ3, Q12906, Q13148, Q13283, Q1ECX4, Q32KX7, Q32LC7, Q3SWT1, Q3ZBD9, Q4R5D9, Q5FVP2, Q5PRC7, Q5R601, Q5R8L2, Q5RB87, Q5SDR3, Q5U2U0, Q5ZLN5, Q64213, Q66K94, Q6DE02, Q6NRF9, Q86UE8, Q8BGW5, Q8BT14, Q8C0V0, Q8R2Y9, Q90ZY6, Q91YT7

Diamond homologs: A0A1P8AS03, E7F1H9, E9Q5K9, F4K1Z0, G4MRQ6, P59326, Q06390, Q0VCZ3, Q3MK94, Q4R5D9, Q5RFL8, Q7Z739, Q8BYK6, Q91YT7, Q96MU7, Q9BYJ9, Q9LJE5, Q9QY02, Q9VBZ5, Q9VZQ1, Q9Y5A9, A0A9P4XWM4, A9LNK9, B2RR83, Q5R746, Q9H6S0, A3KMI0, B4LX81, D4A2Z8, F4HYJ7, F4I9Q5, F4IDQ6, F4ILR7, F4IM84, F4INY4, O17438, O22243, O70133, P0C7L7, P24785

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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
Intrinsic Pathway for Apoptosis	5	14.2×	4e-03
SARS-CoV-1-host interactions	7	11.9×	1e-03
Apoptosis	6	9.8×	5e-03
SARS-CoV-1 Infection	7	9.7×	3e-03
Signaling by ALK fusions and activated point mutants	6	8.8×	7e-03
Programmed Cell Death	6	8.5×	7e-03
SARS-CoV-2-host interactions	7	8.1×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

935 predictions. Top by Δscore:

Variant	Effect	Δscore
1:28737608:A:AG	acceptor_gain	1.0000
1:28737618:T:A	acceptor_gain	1.0000
1:28737619:G:A	acceptor_gain	1.0000
1:28737681:AG:A	donor_gain	1.0000
1:28737682:GG:G	donor_gain	1.0000
1:28737683:G:GG	donor_gain	1.0000
1:28738257:A:AG	acceptor_gain	1.0000
1:28738258:G:GA	acceptor_gain	1.0000
1:28738258:GT:G	acceptor_gain	1.0000
1:28738258:GTA:G	acceptor_gain	1.0000
1:28738258:GTAC:G	acceptor_gain	1.0000
1:28738258:GTACA:G	acceptor_gain	1.0000
1:28738335:GCCC:G	donor_gain	1.0000
1:28738339:G:GG	donor_gain	1.0000
1:28768920:C:G	acceptor_gain	1.0000
1:28768926:TA:T	acceptor_loss	1.0000
1:28768927:A:AC	acceptor_loss	1.0000
1:28768928:G:A	acceptor_loss	1.0000
1:28768928:GGAAC:G	acceptor_gain	1.0000
1:28737609:T:G	acceptor_gain	0.9900
1:28737624:A:G	acceptor_gain	0.9900
1:28737678:CAAAG:C	donor_gain	0.9900
1:28737679:AAAG:A	donor_gain	0.9900
1:28737680:AAG:A	donor_gain	0.9900
1:28738253:CTTTA:C	acceptor_loss	0.9900
1:28738254:TTTA:T	acceptor_loss	0.9900
1:28738255:TTAGT:T	acceptor_loss	0.9900
1:28738256:TAGTA:T	acceptor_loss	0.9900
1:28738261:C:G	acceptor_gain	0.9900
1:28738334:GGCCC:G	donor_gain	0.9900

AlphaMissense

3827 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:28742493:T:A	W75R	1.000
1:28742493:T:C	W75R	1.000
1:28742985:T:A	W239R	1.000
1:28742985:T:C	W239R	1.000
1:28742986:G:C	W239S	1.000
1:28742987:G:C	W239C	1.000
1:28742987:G:T	W239C	1.000
1:28742989:C:A	A240D	1.000
1:28742998:C:A	A243D	1.000
1:28743102:T:A	W278R	1.000
1:28743102:T:C	W278R	1.000
1:28743445:T:C	L392P	1.000
1:28743462:T:G	Y398D	1.000
1:28743467:C:A	N399K	1.000
1:28743467:C:G	N399K	1.000
1:28743502:G:C	R411P	1.000
1:28743505:T:A	V412D	1.000
1:28743507:T:A	F413I	1.000
1:28743507:T:C	F413L	1.000
1:28743507:T:G	F413V	1.000
1:28743508:T:C	F413S	1.000
1:28743509:C:A	F413L	1.000
1:28743509:C:G	F413L	1.000
1:28743510:A:T	I414F	1.000
1:28743511:T:A	I414N	1.000
1:28743511:T:C	I414T	1.000
1:28743511:T:G	I414S	1.000
1:28743513:A:T	I415F	1.000
1:28743514:T:A	I415N	1.000
1:28743514:T:C	I415T	1.000

dbSNP variants (sampled 300 via entrez): RS1000027443 (1:28749587 A>T), RS1000028606 (1:28755085 T>C,G), RS1000165075 (1:28760443 C>A,G,T), RS1000284827 (1:28739264 C>G), RS1000325863 (1:28766184 T>C), RS1000625731 (1:28765426 A>T), RS1000628086 (1:28734869 G>A), RS1000810550 (1:28737196 G>A,C), RS1000852954 (1:28761723 ACT>A), RS1000884202 (1:28740999 C>A,T), RS1000988374 (1:28761416 G>A), RS1001090456 (1:28747891 T>A), RS1001226966 (1:28759551 A>G), RS1001237888 (1:28736211 G>A), RS1001239354 (1:28769698 A>G)

Disease associations

OMIM: gene MIM:610640 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295992 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 7 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.17	Kd	68.45	nM	CHEMBL3752910
7.17	ED50	68.45	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 33 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149967: Binding affinity to human YTHDF2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0684	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, decreases reaction, increases stability, increases reaction, affects reaction (+3 more)	7
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	4
N-methyladenosine	affects binding, decreases reaction, decreases expression, increases abundance	2
Air Pollutants	decreases expression, affects expression, increases abundance	2
Arsenic	increases expression, affects reaction, increases mutagenesis	2
Benzo(a)pyrene	increases expression, increases methylation	2
Indomethacin	increases expression, decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	increases expression	2
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
trichostatin A	affects expression	1
cadmium sulfate	increases expression	1
fumonisin B1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-phenylbutyric acid	decreases expression	1
ICG 001	decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	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
Arsenic Trioxide	increases response to substance	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Acetylcysteine	affects binding, decreases reaction, increases reaction	1
Caffeine	affects phosphorylation	1
Dactinomycin	affects reaction, decreases stability	1
Dexamethasone	affects cotreatment, increases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118957	Binding	Binding affinity to YTHDF2 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8RX	Abcam HCT 116 YTHDF2 KO	Cancer cell line	Male
CVCL_B9UF	Abcam A-549 YTHDF2 KO	Cancer cell line	Male
CVCL_TY47	HAP1 YTHDF2 (-) 1	Cancer cell line	Male
CVCL_XV20	HAP1 YTHDF2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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