CHD4

Summary

CHD4 (chromodomain helicase DNA binding protein 4, HGNC:1919) is a protein-coding gene on chromosome 12p13.31, encoding ATP-dependent chromatin remodeler CHD4 (Q14839). ATP-dependent chromatin-remodeling factor that binds and distorts nucleosomal DNA. It is a common-essential gene (DepMap: required in 96.1% of cancer cell lines).

The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein. Somatic mutations in this gene are associated with serous endometrial tumors. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1108 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 811 total — 14 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 40
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 7 cancer types
• Cancer dependency (DepMap): dependent in 96.1% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001273

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1919
Approved symbol	CHD4
Name	chromodomain helicase DNA binding protein 4
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	Mi-2b, Mi2-BETA
Ensembl gene	ENSG00000111642
Ensembl biotype	protein_coding
OMIM	603277
Entrez	1108

Gene structure

Transcript identifiers

Ensembl transcripts: 69 — 37 protein_coding, 13 retained_intron, 10 protein_coding_CDS_not_defined, 9 nonsense_mediated_decay

ENST00000357008, ENST00000430771, ENST00000535717, ENST00000537634, ENST00000540960, ENST00000544040, ENST00000544484, ENST00000545083, ENST00000545584, ENST00000545942, ENST00000642594, ENST00000642637, ENST00000642686, ENST00000642810, ENST00000642860, ENST00000642879, ENST00000642893, ENST00000643335, ENST00000643367, ENST00000643538, ENST00000643815, ENST00000644077, ENST00000644132, ENST00000644137, ENST00000644289, ENST00000644352, ENST00000644356, ENST00000644652, ENST00000644801, ENST00000645005, ENST00000645022, ENST00000645095, ENST00000645143, ENST00000645199, ENST00000645265, ENST00000645645, ENST00000645717, ENST00000645991, ENST00000646070, ENST00000646145, ENST00000646268, ENST00000646360, ENST00000646366, ENST00000646462, ENST00000646608, ENST00000646609, ENST00000646787, ENST00000646806, ENST00000647112, ENST00000647333, ENST00000647394, ENST00000647426, ENST00000647483, ENST00000647535, ENST00000931042, ENST00000931043, ENST00000931044, ENST00000931045, ENST00000931046, ENST00000931047, ENST00000931048, ENST00000931049, ENST00000931050, ENST00000931051, ENST00000931052, ENST00000931053, ENST00000957179, ENST00000957180, ENST00000957181

RefSeq mRNA: 3 — MANE Select: NM_001273 NM_001273, NM_001297553, NM_001363606

CCDS: CCDS76510, CCDS8552, CCDS86267

Canonical transcript exons

ENST00000544040 — 40 exons

Exon	Start	End
ENSE00000715290	6577785	6577917
ENSE00000715291	6578029	6578137
ENSE00000715292	6578409	6578546
ENSE00000715293	6578846	6578917
ENSE00000715295	6581649	6581814
ENSE00000715296	6582137	6582281
ENSE00000715303	6587712	6587949
ENSE00000715310	6592696	6592817
ENSE00000715311	6593091	6593228
ENSE00000715313	6593416	6593616
ENSE00000715316	6594459	6594650
ENSE00000715318	6595334	6595430
ENSE00000715319	6596006	6596137
ENSE00000715320	6597894	6598099
ENSE00000715321	6598222	6598425
ENSE00000715324	6599773	6600012
ENSE00000715325	6600217	6600395
ENSE00000715327	6600926	6601053
ENSE00000715329	6601289	6601530
ENSE00000715331	6601960	6602175
ENSE00000866931	6581044	6581173
ENSE00000866932	6581291	6581388
ENSE00001183612	6570869	6571032
ENSE00001350281	6583198	6583378
ENSE00001403794	6606274	6606451
ENSE00001627364	6591466	6591583
ENSE00001711290	6588298	6588422
ENSE00001774127	6601648	6601766
ENSE00001792380	6573074	6573269
ENSE00002311082	6607300	6607379
ENSE00003463354	6582848	6582936
ENSE00003508923	6602376	6602497
ENSE00003510356	6583027	6583113
ENSE00003542155	6600534	6600669
ENSE00003549682	6582615	6582748
ENSE00003626201	6587384	6587559
ENSE00003641145	6591916	6592057
ENSE00003665013	6592393	6592566
ENSE00003667095	6591694	6591825
ENSE00003901294	6570082	6570693

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 89.0756 / max 951.4684, expressed in 1827 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129132	70.5707	1827
129133	11.5776	1801
129129	2.7557	1113
129130	1.6046	940
129122	0.9661	524
129126	0.4613	187
129131	0.4395	254
129124	0.4006	215
129128	0.2664	92
129127	0.0330	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.70	gold quality
ganglionic eminence	UBERON:0004023	98.31	gold quality
colonic epithelium	UBERON:0000397	97.93	gold quality
right lobe of thyroid gland	UBERON:0001119	97.92	gold quality
adenohypophysis	UBERON:0002196	97.89	gold quality
sural nerve	UBERON:0015488	97.83	gold quality
apex of heart	UBERON:0002098	97.79	gold quality
right adrenal gland cortex	UBERON:0035827	97.79	gold quality
left lobe of thyroid gland	UBERON:0001120	97.76	gold quality
lower esophagus mucosa	UBERON:0035834	97.70	gold quality
right coronary artery	UBERON:0001625	97.68	gold quality
right adrenal gland	UBERON:0001233	97.67	gold quality
metanephros cortex	UBERON:0010533	97.63	gold quality
right uterine tube	UBERON:0001302	97.62	gold quality
stromal cell of endometrium	CL:0002255	97.61	gold quality
skin of leg	UBERON:0001511	97.57	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.55	gold quality
embryo	UBERON:0000922	97.52	gold quality
left adrenal gland cortex	UBERON:0035825	97.50	gold quality
right testis	UBERON:0004534	97.46	gold quality
left adrenal gland	UBERON:0001234	97.45	gold quality
thyroid gland	UBERON:0002046	97.43	gold quality
tibial nerve	UBERON:0001323	97.41	gold quality
right ovary	UBERON:0002118	97.39	gold quality
mucosa of stomach	UBERON:0001199	97.38	gold quality
skin of abdomen	UBERON:0001416	97.36	gold quality
adrenal cortex	UBERON:0001235	97.35	gold quality
ectocervix	UBERON:0012249	97.34	gold quality
descending thoracic aorta	UBERON:0002345	97.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.90
E-MTAB-7008	no	248.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
BCL11A	Repression
CD79A	Repression
HBG1	Repression
HBG2	Repression
KCTD16
RNF8	Unknown

Upstream regulators (CollecTRI, top): CUX1, EGR2, EZH2, FOXN1, GATA3, GLI3, JUN, MBD2, PARP1, ZFHX4, ZNF410

miRNA regulators (miRDB)

73 targeting CHD4, 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-12118	100.00	65.88	1270
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 96.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• the amino-terminal and carboxyl-terminal regions of Mi-2 beta have distinct transcriptional activities and bind to BRG1 and the RET finger protein, forming a multiprotein supercomplex involved in transcriptional regulation. (PMID:14530259)
• Mi-2beta and RFP, known to be involved in transcriptional repression in the nucleus, co-localize with MCRS1 in the nucleolus and appear to activate the rRNA transcription. (PMID:16186106)
• Pericentrin forms complexes with CHD3 and CHD4, but a distinct CHD3-pericentrin complex is required for centrosomal anchoring of pericentrin/gamma-tubulin and for centrosome integrity. (PMID:17626165)
• The known subunits of the Mi-2/NuRD complex , their connections to signaling networks, and their association with cancer are reviewed. (PMID:17694084)
• PU.1 directs Mi2beta to erase an established DNase I-hypersensitive site, in an ATP-dependent reaction subsequent to PU.1 binding to chromatin, whereas ACF will not support erasure (PMID:19158090)
• Data show that Mi-2/NuRD constitutes an enzymatic component of a pathway for assembly and maturation of chromatin utilized by rapidly proliferating lymphoid cells for replication of constitutive heterochromatin. (PMID:19296121)
• The PHD2 finger plays a role in targeting of the CHD4/NuRD complex to chromatin. (PMID:19624289)
• CHD4 could bind to two H3 N-terminal tails on the same nucleosome or on two separate nucleosomes simultaneously, presenting exciting implications for the mechanism by which CHD4 and the NuRD complex could direct chromatin remodeling. (PMID:21278251)
• Chd4 is necessary to guide proper terminal differentiation of Schwann cells; the nucleosome remodeling and deacetylase (NURD) complex is a requisite factor in timely and stable peripheral chromatin remodeling. (PMID:22302795)
• a three-dimensional structural model describing the overall shape and domain interactions of CHD4 and discuss the relevance of these for regulating the remodeling of chromatin by the NuRD complex. (PMID:22575888)
• Concerted action of the PHD, chromo and motor domains regulates the human chromatin remodelling ATPase CHD4 (PMID:22749909)
• repressive functions of MBD2-containing NuRD complexes are dependent on cooperative interactions between the major domains of CHD4 with histones and DNA and on binding of methylated DNA by MBD2 (PMID:23071088)
• CHD4 and HDAC1 occupy the promoters of several of these hypermethylated tumor suppressor genes and physically and functionally interact to maintain their silencing. (PMID:23708667)
• Endogenous Mta1/2 forms a complex with chromodomain helicase (Chd)4, histone deacetylases (Hdac)1/2, RbAp46/48, and Mbd3 in rat cerebellum (PMID:24991957)
• D140E SNP was associated with lung cancer, malignant lymphoma and rectum cancer and may interact with smoking habit to increase the risk. (PMID:25407497)
• CHD4 modulates therapeutic response in BRCA2 mutant cancer cells. (PMID:25737278)
• CHD4 plays a pivotal role in chemoresistance and the maintenance of stemness in liver cancer stem cells and is therefore a good target for the eradication of hepatocellular carcinoma. (PMID:26095183)
• CHD4 depletion modulates expression of acute myeloid leukemia cell genes that regulate tumor formation in vivo and colony formation in vitro. (PMID:26265695)
• Also discovered a novel causative role for CHD4, a helicase involved in the histone deacetylase complex that is associated with poor clinical outcome. (PMID:26296641)
• Acetyltransferase p300 collaborates with chromodomain helicase DNA-binding protein 4 (CHD4) to facilitate DNA double-strand break repair (PMID:26546801)
• these data build on our understanding of how CHD4-NuRD acts to regulate gene expression and participates in the DNA-damage response. (PMID:26565020)
• Specifically, methyl-CpG-binding domain protein 2 (MBD2) is revealed to be recruited to DNA damage sites after laser microirradiation, which was mediated through MBD domain and MBD2 C-terminus. (PMID:26827827)
• complex lacking CHD4 that has HDAC activity can exist as a stable species. The addition of recombinant CHD4 to this nucleosome deacetylase complex reconstitutes a NuRD complex with nucleosome remodeling activity. (PMID:27235397)
• Mutation in CHD4 gene is associated with congenital heart defects. (PMID:27479907)
• report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification (PMID:27616479)
• this work identifies CHD4 as an epigenetic coregulator of PAX3-FOXO1 activity, providing rational evidence for CHD4 as a potential therapeutic target in alveolar rhabdomyosarcoma. (PMID:27760049)
• RNA interference identifies CHD4 as an essential gene in regulating breast cancer growth. (PMID:27779108)
• this study identifies the Chd4-Tbx3 axis in controlling ESC fate and a role of H2A.Z in maintaining the stability of Chd4 proteins. (PMID:28298436)
• CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. (PMID:28486105)
• the results indicated that different location of CHD4 staining is a potential biomarker to differentiate cellular schwannoma from malignant peripheral sheath tumor. (PMID:28549031)
• The findings identify that CHD4 deficiency preferentially impairs cell survival via increasing the level of p21. (PMID:28842166)
• CHD3 and CHD4 exhibit distinct nuclear localization patterns in unperturbed cells, revealing a subset of specific target genes. (PMID:28977666)
• Data suggest TCF19 interacts with histone 3 lysine 4 trimethylation through its plant homeodomain finger; TCF19 expression appears to regulate gluconeogenesis in hepatocytes; TCF19 interacts with CHD4 causing NuRD complex recruitment to gene promoters of enzymes involved in gluconeogenesis. (TCF19 = transcription factor 19; CHD4 = chromodomain helicase DNA binding protein 4; NuRD = nucleosome-remodeling-deacetylase) (PMID:29042441)
• Alterations of EZH2, KMT2C, and CHD4 at genetic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. (PMID:29272522)
• that CHD4 is not only a potential prognostic biomarker for triple-negative breast cancer (TNBC) patient survival, but is also a powerful candidate in the development of new anti-cancer agents in TNBC (PMID:29305962)
• CHD4 is essential for maintenance of childhood AML and the LICs that are responsible for the emergence and development of the disease. Our data indicate that the importance of CHD4 in childhood AML may be mediated in part by promoting the expression of the MYC oncogene and its target genes. (PMID:29599201)
• the N-terminal part of CHD4 interacts with an unstructured A-rich region in promoter and pre-rRNA antisense “), a long noncoding RNA that is transcribed in an orientation antisense to pre-rRNA (PMID:29907651)
• CHD4 regulates the DNA damage response and RAD51 expression in glioblastoma. (PMID:30872624)
• The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. (PMID:31474762)
• Functional interactions between Mi-2beta and AP1 complexes control response and recovery from skin barrier disruption. (PMID:31834931)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	chd4a	ENSDARG00000063535
mus_musculus	Chd4	ENSMUSG00000063870
rattus_norvegicus	Chd4	ENSRNOG00000018309

Paralogs (30): HLTF (ENSG00000071794), SMARCA2 (ENSG00000080503), SRCAP (ENSG00000080603), ATRX (ENSG00000085224), RAD54L (ENSG00000085999), BTAF1 (ENSG00000095564), CHD8 (ENSG00000100888), SMARCA1 (ENSG00000102038), CHD5 (ENSG00000116254), TTF2 (ENSG00000116830), HELLS (ENSG00000119969), ZRANB3 (ENSG00000121988), CHD6 (ENSG00000124177), SMARCA4 (ENSG00000127616), INO80 (ENSG00000128908), CHD1L (ENSG00000131778), SMARCAL1 (ENSG00000138375), SHPRH (ENSG00000146414), SMARCA5 (ENSG00000153147), CHD1 (ENSG00000153922), SMARCAD1 (ENSG00000163104), RAD54L2 (ENSG00000164080), CHD3 (ENSG00000170004), CHD7 (ENSG00000171316), CHD2 (ENSG00000173575), CHD9 (ENSG00000177200), EP400 (ENSG00000183495), ERCC6L (ENSG00000186871), RAD54B (ENSG00000197275), ERCC6 (ENSG00000225830)

Protein

Protein identifiers

ATP-dependent chromatin remodeler CHD4 — Q14839 (reviewed: Q14839)

Alternative names: Chromo domain-containing protein 4, Mi-2 autoantigen 218 kDa protein, Mi2-beta

All UniProt accessions (30): Q14839, A0A0C4DGG9, A0A2R8Y212, A0A2R8Y425, A0A2R8Y4X2, A0A2R8Y512, A0A2R8Y521, A0A2R8Y539, A0A2R8Y5J0, A0A2R8Y5M9, A0A2R8Y5Z7, A0A2R8Y685, A0A2R8Y6G9, A0A2R8Y795, A0A2R8Y7I0, A0A2R8Y7M9, A0A2R8Y7X1, A0A2R8Y8B3, A0A2R8Y8C1, A0A2R8YD40, A0A2R8YDJ9, A0A2R8YDW2, A0A2R8YE38, A0A2R8YER1, A0A2R8YFD8, A0A2R8YFK9, A0A2U3TZM0, F5GWX5, F5H596, F5H6N4

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent chromatin-remodeling factor that binds and distorts nucleosomal DNA. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Localizes to acetylated damaged chromatin in a ZMYND8-dependent manner, to promote transcriptional repression and double-strand break repair by homologous recombination. Involved in neurogenesis.

Subunit / interactions. Component of the nucleosome remodeling and deacetylase (NuRD) repressor complex, composed of core proteins MTA1, MTA2, MTA3, RBBP4, RBBP7, HDAC1, HDAC2, MBD2, MBD3, and peripherally associated proteins CDK2AP1, CDK2AP2, GATAD2A, GATAD2B, CHD3, CHD4 and CHD5. The exact stoichiometry of the NuRD complex is unknown, and some subunits such as MBD2 and MBD3, GATAD2A and GATAD2B, and CHD3, CHD4 and CHD5 define mutually exclusive NuRD complexes. Interacts with IKFZ1; the interaction is direct and when in part of the NuRD complex. Part of a complex containing ATR and HDAC2. Interacts with HDAC2; the interaction is direct. Interacts with the cohesin complex component RAD21; the interaction is direct. Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct. Interacts with ZGPAT; the interaction is direct. Interacts with ZMYND8; the interaction is direct, appears to occur with monomeric ZMYND8, and is increased following DNA damage. Interacts with BCL6. Interacts with BRD4. Interacts with CBX1. Interacts with CBX3. Interacts with CBX5. Interacts with GATAD2A. Interacts with HDAC1. Interacts with KLF1; the interaction depends on sumoylation of KLF1, and leads to its transcriptional repression. Interacts with MTA1. Interacts with PCNT. Interacts with RBBP7. Interacts with SETX. Interacts with TRIM27. Interacts with histone H3. Interacts with histone H4. Does not interact with PWWP2A. Does not interact with PWWP2B. Interacts (via KIKL motif) with BRD3 (via NET domain).

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Widely expressed.

Disease relevance. Sifrim-Hitz-Weiss syndrome (SIHIWES) [MIM:617159] An autosomal dominant syndrome characterized by intellectual disability, variable congenital defects affecting cardiac, skeletal, and urogenital systems. Short stature, macrocephaly, hearing impairment, and facial dysmorphism are present in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The KIKL motif recognizes and binds the NET domain of BRD3.

Miscellaneous. One of the main antigens reacting with anti-MI-2 positive sera of dermatomyositis.

Similarity. Belongs to the SNF2/RAD54 helicase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14839-1	1	yes
Q14839-2	2

RefSeq proteins (3): NP_001264, NP_001284482, NP_001350535 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR000953	Chromo/chromo_shadow_dom	Domain
IPR001650	Helicase_C-like	Domain
IPR001965	Znf_PHD	Domain
IPR002464	DNA/RNA_helicase_DEAH_CS	Conserved_site
IPR009462	CHD_II_SANT-like	Domain
IPR009463	DUF1087	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR012957	CHD_C2	Domain
IPR012958	CHD_N	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR014001	Helicase_ATP-bd	Domain
IPR016197	Chromo-like_dom_sf	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR023780	Chromo_domain	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR038718	SNF2-like_sf	Homologous_superfamily
IPR049730	SNF2/RAD54-like_C	Domain

Pfam: PF00176, PF00271, PF00385, PF00628, PF06461, PF06465, PF08073, PF08074

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (199 total): helix 49, strand 38, modified residue 29, cross-link 27, turn 16, sequence variant 10, region of interest 9, compositionally biased region 9, domain 4, short sequence motif 2, zinc finger region 2, chain 1, binding site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6Q3M	X-RAY DIFFRACTION	2.52
4O9I	X-RAY DIFFRACTION	2.6
8D4Y	X-RAY DIFFRACTION	2.9
6RYR	ELECTRON MICROSCOPY	3.1
6RYU	ELECTRON MICROSCOPY	4
1MM2	SOLUTION NMR
1MM3	SOLUTION NMR
2EE1	SOLUTION NMR
2L5U	SOLUTION NMR
2L75	SOLUTION NMR
2N5N	SOLUTION NMR
6BGG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14839-F1	65.41	0.17

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 (1): 751–758

Post-translational modifications (56): 44, 303, 308, 309, 310, 319, 367, 428, 515, 517, 529, 531, 703, 1209, 1308, 1349, 1370, 1531, 1535, 1537 …

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-3214815	HDACs deacetylate histones
R-HSA-427389	ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
R-HSA-6804758	Regulation of TP53 Activity through Acetylation
R-HSA-73762	RNA Polymerase I Transcription Initiation
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-9031628	NGF-stimulated transcription
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9843940	Regulation of endogenous retroelements by KRAB-ZFP proteins
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
R-HSA-9845323	Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)
R-HSA-9937850	NuRD complex assembly
R-HSA-9940465	ChAHP complex assembly
R-HSA-9940951	Interaction of NuRD complexes with transcription factors
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

MSigDB gene sets: 460 (showing top): PID_HDAC_CLASSI_PATHWAY, CREL_01, GOBP_SYNAPSE_ASSEMBLY, MORF_UBE2I, REACTOME_RNA_POLYMERASE_I_TRANSCRIPTION_INITIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MORF_HDAC1, MORF_UBE2N, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, AP2_Q3, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), double-strand break repair via homologous recombination (GO:0000724), chromatin remodeling (GO:0006338), negative regulation of gene expression (GO:0010629), regulation of cell fate specification (GO:0042659), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), regulation of synapse assembly (GO:0051963), terminal button organization (GO:0072553), regulation of stem cell differentiation (GO:2000736), chromatin organization (GO:0006325), oxygen transport (GO:0015671)

GO Molecular Function (18): transcription coregulator binding (GO:0001221), DNA binding (GO:0003677), chromatin binding (GO:0003682), transcription corepressor activity (GO:0003714), ATP binding (GO:0005524), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), histone binding (GO:0042393), histone deacetylase binding (GO:0042826), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), ATP-dependent chromatin remodeler activity (GO:0140658), nucleotide binding (GO:0000166), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), nucleosomal DNA binding (GO:0031492), metal ion binding (GO:0046872), DNA-binding transcription factor binding (GO:0140297)

GO Cellular Component (13): chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), membrane (GO:0016020), NuRD complex (GO:0016581), protein-containing complex (GO:0032991), RNA polymerase II transcription regulator complex (GO:0090575), site of DNA damage (GO:0090734), cerebellar granule cell to Purkinje cell synapse (GO:0150048), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Regulation of endogenous retroelements	2
CHD3, CHD4, CHD5 subfamily	2
Chromatin modifying enzymes	1
Positive epigenetic regulation of rRNA expression	1
Regulation of TP53 Activity	1
RNA Polymerase I Promoter Clearance	1
PTEN Regulation	1
Nuclear Events (kinase and transcription factor activation)	1
SARS-CoV Infections	1
Transcriptional regulation of brown and beige adipocyte differentiation	1
NuRD complex assembly	1
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
negative regulation of DNA-templated transcription	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
transcription factor binding	2
binding	2
ATP-dependent activity	2
chromosome	2
transcription regulator complex	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
recombinational repair	1
double-strand break repair	1
chromatin organization	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
cell fate specification	1
regulation of cell fate commitment	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
synapse assembly	1
regulation of synapse organization	1
regulation of cell junction assembly	1
presynapse organization	1
regulation of cell differentiation	1
stem cell differentiation	1
cellular component organization	1
gas transport	1
nucleic acid binding	1
transcription coregulator activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
enzyme binding	1
DNA-binding transcription factor binding	1
DNA binding	1
chromatin remodeling	1

Protein interactions and networks

STRING

4613 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHD4	RBBP4	P31149	998
CHD4	MTA2	O94776	997
CHD4	MTA1	Q13330	997
CHD4	RBBP7	Q16576	997
CHD4	HDAC1	Q13547	996
CHD4	HDAC2	Q92769	994
CHD4	GATAD2A	Q86YP4	987
CHD4	CHD3	Q12873	983
CHD4	KDM1A	O60341	972
CHD4	GATAD2B	Q8WXI9	970
CHD4	MTA3	Q9BTC8	968
CHD4	ADNP	Q9H2P0	954
CHD4	EZH2	Q15910	938
CHD4	BRD4	O60885	915
CHD4	MCRS1	Q96EZ8	888

IntAct

253 interactions, top by confidence:

A	B	Type	Score
CHD4	HDAC1	psi-mi:“MI:0403”(colocalization)	0.930
HDAC1	RBBP4	psi-mi:“MI:0914”(association)	0.920
HDAC1	KDM1A	psi-mi:“MI:0914”(association)	0.910
HDAC2	KDM1A	psi-mi:“MI:0914”(association)	0.890
HDAC1	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
RBBP7	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
CHD4	CBX1	psi-mi:“MI:0914”(association)	0.790
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
HDAC1	TNRC18	psi-mi:“MI:0914”(association)	0.790
GATAD2B	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
CHD4	CDK2AP1	psi-mi:“MI:0914”(association)	0.730
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
GATAD2A	CDK2AP1	psi-mi:“MI:0914”(association)	0.730
CDK2AP1	MTA2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CHD4	RBBP7	psi-mi:“MI:0403”(colocalization)	0.680
CBX3	E2F6	psi-mi:“MI:0914”(association)	0.640
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
ZNF219	CDK2AP1	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
GATAD2B	MTA2	psi-mi:“MI:0914”(association)	0.640
CHD4	MTA2	psi-mi:“MI:0914”(association)	0.630

BioGRID (1531): HIST1H3A (Co-crystal Structure), HIST1H3A (Protein-peptide), CHD4 (Affinity Capture-Western), CHD4 (Affinity Capture-MS), CHD4 (Affinity Capture-Western), ZFHX4 (Affinity Capture-Western), MTA1 (Affinity Capture-Western), CHD4 (Protein-peptide), CHD4 (Affinity Capture-MS), CHD4 (Affinity Capture-MS), CHD4 (Affinity Capture-MS), CHD4 (Affinity Capture-MS), CHD4 (Affinity Capture-MS), CHD4 (Affinity Capture-MS), CHD4 (Affinity Capture-MS)

ESM2 similar proteins: A2A8L1, A2BGR3, A3KFM7, A7E320, B2RRD7, D3ZA12, D3ZD32, E1B7X9, E7EZF3, F4J9M5, F4JTF6, F4K128, F8VPZ5, G5EBZ4, G5EDG2, O14139, O75164, O97159, P32657, P34305, P38144, P55201, Q03468, Q12873, Q14839, Q22516, Q27746, Q4P3S3, Q5RD88, Q640I9, Q6P1G2, Q6P5D3, Q6PDQ2, Q6ZRS2, Q7G8Y3, Q7TMI3, Q7TPK1, Q7Z478, Q8BRB7, Q8TD26

Diamond homologs: A0A0P0WGX7, A2A8L1, A2BGR3, A3KFM7, A6QQR4, A7Z019, A9X4T1, B0R0I6, B0XPE7, B3NAN8, B4GS98, B5BT18, B5DE69, B6ZLK2, D3Z9Z9, D3ZA12, D3ZD32, E1B7X9, F1Q8K0, F4I2H2, F4IV45, F4J9M5, F4JY24, F4K128, F4KBP5, F8VPZ5, G5EBZ4, G5EF53, O12944, O13682, O14139, O14646, O14981, O43065, O76460, P0CO16, P0CO17, P28370, P31380, P32333

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CHD4	“form complex”	“MBD2/NuRD complex”	binding
CHD4	“form complex”	“MBD3/NuRD complex”	binding
CHD4	“down-regulates quantity by repression”	CD79A	“transcriptional regulation”
MBD2	“down-regulates quantity by repression”	CHD4	“transcriptional regulation”
CHD4	“form complex”	ChAHP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 207 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
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	10	25.7×	3e-10
Regulation of TP53 Activity through Acetylation	8	24.7×	4e-08
Regulation of PTEN gene transcription	14	16.9×	1e-11
RNA Polymerase I Transcription Initiation	11	16.6×	3e-09
NuRD complex assembly	16	15.2×	4e-12
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	15	14.8×	1e-11
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	14	14.4×	9e-11
Transcriptional Regulation by E2F6	7	13.8×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of stem cell differentiation	11	44.8×	7e-14
DNA methylation-dependent constitutive heterochromatin formation	5	14.5×	2e-03
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	6	12.8×	8e-04
heterochromatin formation	8	10.9×	1e-04
chromatin remodeling	22	8.5×	4e-12
circadian regulation of gene expression	6	7.5×	9e-03
protein import into nucleus	9	6.9×	8e-04
nucleosome assembly	9	6.7×	8e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 7 cancer types — ALL, CCRCC, COAD, HNSC, NBL, UCEC, UCS.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	51
Uncertain significance	387
Likely benign	197
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067691	NM_001273.5(CHD4):c.3441C>G (p.Asp1147Glu)	Pathogenic
1805406	NM_001273.5(CHD4):c.4018C>T (p.Arg1340Cys)	Pathogenic
266124	NM_001273.5(CHD4):c.3203G>A (p.Arg1068His)	Pathogenic
266125	NM_001273.5(CHD4):c.2552C>A (p.Ser851Tyr)	Pathogenic
266126	NM_001273.5(CHD4):c.3380G>A (p.Arg1127Gln)	Pathogenic
266127	NM_001273.5(CHD4):c.3518G>T (p.Arg1173Leu)	Pathogenic
266128	NM_001273.5(CHD4):c.3443G>T (p.Trp1148Leu)	Pathogenic
3343123	NM_001273.5(CHD4):c.1409C>T (p.Ser470Phe)	Pathogenic
3572891	NM_001273.5(CHD4):c.3655del (p.Leu1219fs)	Pathogenic
3769589	CHD4, TRP557TER	Pathogenic
4082567	NM_001273.5(CHD4):c.3748G>A (p.Asp1250Asn)	Pathogenic
422591	NM_001273.5(CHD4):c.2659C>T (p.Arg887Trp)	Pathogenic
916063	NM_001273.5(CHD4):c.2862G>A (p.Met954Ile)	Pathogenic
975671	NM_001273.5(CHD4):c.3280G>A (p.Glu1094Lys)	Pathogenic
1030326	NM_001273.5(CHD4):c.3539T>G (p.Val1180Gly)	Likely pathogenic
1186273	NM_001273.5(CHD4):c.4256G>A (p.Arg1419His)	Likely pathogenic
1301898	NM_001273.5(CHD4):c.2648C>T (p.Ser883Phe)	Likely pathogenic
1303840	NM_001273.5(CHD4):c.2949-1G>A	Likely pathogenic
1324066	NM_001273.5(CHD4):c.2313+2T>C	Likely pathogenic
1326016	NM_001273.5(CHD4):c.1714C>T (p.Arg572Ter)	Likely pathogenic
1326839	NM_001273.5(CHD4):c.1483-2A>G	Likely pathogenic
1709214	NM_001273.5(CHD4):c.4003A>C (p.Lys1335Gln)	Likely pathogenic
1804883	NM_001273.5(CHD4):c.2366A>G (p.Asn789Ser)	Likely pathogenic
1806223	NM_001273.5(CHD4):c.3338A>G (p.Asn1113Ser)	Likely pathogenic
2412787	NM_001273.5(CHD4):c.3653T>C (p.Ile1218Thr)	Likely pathogenic
2444444	NM_001273.5(CHD4):c.2239A>G (p.Thr747Ala)	Likely pathogenic
2577975	NM_001273.5(CHD4):c.3290A>T (p.Asp1097Val)	Likely pathogenic
2578331	NM_001273.5(CHD4):c.1895_1896del	Likely pathogenic
2584494	NM_001273.5(CHD4):c.2921_2922del (p.Val974fs)	Likely pathogenic
2633887	NM_001273.5(CHD4):c.3202C>A (p.Arg1068Ser)	Likely pathogenic

SpliceAI

5405 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6570863:TCCTA:T	donor_loss	1.0000
12:6570864:CCTA:C	donor_loss	1.0000
12:6570865:CTAC:C	donor_loss	1.0000
12:6570866:TAC:T	donor_loss	1.0000
12:6570867:A:C	donor_loss	1.0000
12:6570868:C:CG	donor_loss	1.0000
12:6570868:CCTG:C	donor_gain	1.0000
12:6571028:CAGAA:C	acceptor_gain	1.0000
12:6571029:AGAA:A	acceptor_gain	1.0000
12:6571030:GAA:G	acceptor_gain	1.0000
12:6571031:AA:A	acceptor_gain	1.0000
12:6571033:C:CC	acceptor_gain	1.0000
12:6571036:CA:C	acceptor_gain	1.0000
12:6571037:A:AC	acceptor_gain	1.0000
12:6571037:A:C	acceptor_gain	1.0000
12:6573105:T:A	donor_gain	1.0000
12:6573266:AGAG:A	acceptor_gain	1.0000
12:6573267:GAG:G	acceptor_gain	1.0000
12:6573268:AG:A	acceptor_gain	1.0000
12:6573270:C:CC	acceptor_gain	1.0000
12:6573275:C:CT	acceptor_gain	1.0000
12:6577934:C:CT	acceptor_gain	1.0000
12:6577935:A:T	acceptor_gain	1.0000
12:6578027:A:AC	donor_gain	1.0000
12:6578028:C:CG	donor_gain	1.0000
12:6578463:T:TA	donor_gain	1.0000
12:6578474:T:C	donor_gain	1.0000
12:6578542:CTCTT:C	acceptor_gain	1.0000
12:6578543:TCTT:T	acceptor_loss	1.0000
12:6578544:CTT:C	acceptor_gain	1.0000

AlphaMissense

12699 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6570903:A:G	L1896P	1.000
12:6570912:A:G	L1893P	1.000
12:6570912:A:T	L1893H	1.000
12:6570915:A:G	I1892T	1.000
12:6570915:A:T	I1892N	1.000
12:6570924:T:A	E1889V	1.000
12:6570936:A:G	L1885S	1.000
12:6570948:A:T	V1881D	1.000
12:6570978:A:G	L1871P	1.000
12:6570978:A:T	L1871H	1.000
12:6570991:C:G	D1867H	1.000
12:6570999:A:C	M1864R	1.000
12:6570999:A:T	M1864K	1.000
12:6571003:C:G	D1863H	1.000
12:6571008:A:G	L1861P	1.000
12:6571008:A:T	L1861Q	1.000
12:6571011:A:G	L1860P	1.000
12:6571020:A:G	L1857P	1.000
12:6571029:A:G	L1854P	1.000
12:6573082:A:G	L1850P	1.000
12:6573085:A:T	V1849D	1.000
12:6573094:G:T	A1846D	1.000
12:6573119:C:T	E1838K	1.000
12:6573127:A:G	L1835P	1.000
12:6573127:A:T	L1835Q	1.000
12:6573137:G:C	H1832D	1.000
12:6573138:A:C	S1831R	1.000
12:6573138:A:T	S1831R	1.000
12:6573140:T:G	S1831R	1.000
12:6573146:C:G	A1829P	1.000

dbSNP variants (sampled 300 via entrez): RS1000043474 (12:6575861 A>G), RS1000118366 (12:6578536 TTTC>T), RS1000126013 (12:6589298 C>T), RS1000170786 (12:6590738 T>C,G), RS1000201849 (12:6590901 G>C), RS1000240982 (12:6588976 A>G), RS1000418688 (12:6584781 G>A,T), RS1000445608 (12:6600083 C>A,G,T), RS1000457618 (12:6588026 C>T), RS1000537694 (12:6589864 TAA>T), RS1000552859 (12:6582786 C>T), RS1000676281 (12:6601147 T>C), RS1000783951 (12:6598666 G>A,C), RS1000795630 (12:6594808 T>C), RS1000850871 (12:6596921 T>C)

Disease associations

OMIM: gene MIM:603277 | disease phenotypes: MIM:617159

GenCC curated gene-disease

Disease	Classification	Inheritance
Sifrim-Hitz-Weiss syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (4): Sifrim-Hitz-Weiss syndrome (MONDO:0014946), intellectual disability (MONDO:0001071), cleft palate (MONDO:0016064), coloboma (MONDO:0001476)

Orphanet (4): CHD4-related neurodevelopmental disorder (Orphanet:653712), Cleft palate (Orphanet:2014), OBSOLETE: Ocular coloboma (Orphanet:194), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000193	Bifid uvula
HP:0000243	Trigonocephaly
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000483	Astigmatism
HP:0000508	Ptosis
HP:0000582	Upslanted palpebral fissure
HP:0000894	Short clavicles
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001545	Anteriorly placed anus
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001636	Tetralogy of Fallot
HP:0001643	Patent ductus arteriosus
HP:0001680	Coarctation of aorta

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001712_30	Myopia (pathological)	6.000000e-06
GCST006979_883	Heel bone mineral density	2.000000e-09
GCST90002397_414	Mean spheric corpuscular volume	4.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia
EFO:0009270	heel bone mineral density

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105742 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,795 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 8 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.72	Kd	1.891	nM	CHEMBL3752910
8.72	ED50	1.891	nM	CHEMBL3752910
8.52	Kd	3	nM	DINACICLIB
7.10	IC50	80	nM	MOLIBRESIB
6.21	Kd	614.9	nM	CHEMBL5653589
6.21	ED50	614.9	nM	CHEMBL5653589

PubChem BioAssay actives

4 with measured affinity, of 228 total; 4 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	2148068: Binding affinity to human CHD4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0019	uM
2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol	1424952: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0030	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178757: Inhibition of CHD4 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0800	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148068: Binding affinity to human CHD4 incubated for 45 mins by Kinobead based pull down assay	kd	0.6149	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
bisphenol S	decreases methylation, affects cotreatment, decreases expression	2
Cadmium Chloride	increases expression	2
Particulate Matter	increases expression, increases abundance	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
bufotalin	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
bisphenol A	increases methylation	1
hexamethylene bisacetamide	affects binding, affects cotreatment, decreases reaction, increases O-linked glycosylation, decreases O-linked glycosylation	1
beta-lapachone	decreases expression, increases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	affects phosphorylation	1
perfluorodecanoic acid	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
torcetrapib	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
thiamet G	decreases reaction, increases O-linked glycosylation, affects cotreatment, affects binding, increases reaction	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment, decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 9 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991665	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science
CHEMBL5304679	Functional	Measurement of the ATPase catalytic activity using the ADP-Glo detection (CDH4)	Data for DCP probe FHT-2344

Cellosaurus cell lines

5 cell lines: 4 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1621	OCUB-M	Cancer cell line	Female
CVCL_A0R1	SEES3-1V human CHD4, clone1	Embryonic stem cell	Male
CVCL_A0R2	SEES3-1V human CHD4, clone2	Embryonic stem cell	Male
CVCL_A0R3	SEES3-1V human CHD4, clone3	Embryonic stem cell	Male
CVCL_D0PJ	WAe025-A-1	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02422056	PHASE4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	PHASE4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	PHASE4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	PHASE4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	PHASE3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	PHASE3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00004639	PHASE2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT00760006	PHASE2	COMPLETED	Preventing Complications in Cleft Palate Repair With Antibiotics
NCT01760330	PHASE2	WITHDRAWN	IV Acetaminophen in Children Undergoing Palatoplasty
NCT02350803	PHASE2	COMPLETED	Does Use of Rigid Fixation After Removing Distraction Osteogenesis Device Reduce the Relapse?
NCT03412474	PHASE2	COMPLETED	Suprazygomatic Block in Cleft Palate Surgery in Children
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic