ZBTB7A

Summary

ZBTB7A (zinc finger and BTB domain containing 7A, HGNC:18078) is a protein-coding gene on chromosome 19p13.3, encoding Zinc finger and BTB domain-containing protein 7A (O95365). Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation. It is a selective cancer dependency (DepMap: 20.2% of cell lines).

Enables several functions, including SMAD binding activity; nuclear androgen receptor binding activity; and transcription corepressor binding activity. Involved in several processes, including erythrocyte maturation; negative regulation of signal transduction; and regulation of nucleobase-containing compound metabolic process. Located in cytoplasm and nucleus.

Source: NCBI Gene 51341 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 152 total — 13 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 20.2% of screened cell lines
• Transcription factor: yes — 39 downstream targets (CollecTRI)
• MANE Select transcript: NM_015898

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18078
Approved symbol	ZBTB7A
Name	zinc finger and BTB domain containing 7A
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FBI-1, LRF, DKFZp547O146, pokemon, ZNF857A
Ensembl gene	ENSG00000178951
Ensembl biotype	protein_coding
OMIM	605878
Entrez	51341

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 18 protein_coding

ENST00000322357, ENST00000601588, ENST00000906042, ENST00000906043, ENST00000906044, ENST00000906045, ENST00000906046, ENST00000906047, ENST00000923451, ENST00000923452, ENST00000963793, ENST00000963794, ENST00000963795, ENST00000963796, ENST00000963797, ENST00000963798, ENST00000963799, ENST00000963800

RefSeq mRNA: 2 — MANE Select: NM_015898 NM_001317990, NM_015898

CCDS: CCDS12119

Canonical transcript exons

ENST00000322357 — 3 exons

Exon	Start	End
ENSE00001263603	4066682	4066899
ENSE00001263639	4043303	4048244
ENSE00001422884	4053971	4055247

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.7535 / max 416.4947, expressed in 1810 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178409	8.9879	1708
178405	7.6703	1751
178411	2.3304	1130
178406	1.3341	704
178410	0.7800	427
178407	0.6567	346
178412	0.5018	221
178408	0.4922	244

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.85	gold quality
tendon of biceps brachii	UBERON:0008188	99.51	gold quality
nipple	UBERON:0002030	97.55	gold quality
medial globus pallidus	UBERON:0002477	97.54	gold quality
middle temporal gyrus	UBERON:0002771	97.12	gold quality
pharyngeal mucosa	UBERON:0000355	97.02	gold quality
globus pallidus	UBERON:0001875	96.94	gold quality
pylorus	UBERON:0001166	96.82	gold quality
cerebellar vermis	UBERON:0004720	96.61	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.43	gold quality
cardia of stomach	UBERON:0001162	96.28	gold quality
mammalian vulva	UBERON:0000997	95.48	gold quality
primary visual cortex	UBERON:0002436	95.45	gold quality
occipital lobe	UBERON:0002021	95.13	gold quality
superior surface of tongue	UBERON:0007371	95.03	gold quality
ventral tegmental area	UBERON:0002691	95.01	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.92	gold quality
body of tongue	UBERON:0011876	94.87	gold quality
pons	UBERON:0000988	94.81	gold quality
seminal vesicle	UBERON:0000998	94.61	gold quality
tongue	UBERON:0001723	94.36	gold quality
renal medulla	UBERON:0000362	94.28	gold quality
inferior vagus X ganglion	UBERON:0005363	94.22	gold quality
parietal lobe	UBERON:0001872	94.20	gold quality
pericardium	UBERON:0002407	94.20	gold quality
entorhinal cortex	UBERON:0002728	94.14	gold quality
superior vestibular nucleus	UBERON:0007227	94.09	gold quality
lateral globus pallidus	UBERON:0002476	94.03	gold quality
trigeminal ganglion	UBERON:0001675	93.88	gold quality
gingival epithelium	UBERON:0001949	93.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	27.52
E-ANND-3	yes	9.21

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

39 targets.

Target	Regulation
ACVR1
ADH5	Repression
ADRA1D
BCL2L11
CCNA2	Repression
CDK2	Unknown
CDKN1A	Repression
CDKN2A	Repression
COMP
DUSP1
E2F4	Unknown
ELN
FASN	Activation
FOS	Repression
GHRHR
H19
HCFC1
IL5
INS
MAPK11	Activation
MBD3
MDM2
MIA
MMP14
MMP9
MYC	Repression
NFKBIA
NRIP1
PFKP	Repression
PKM	Repression

JASPAR motifs

Motif	Name	Family
MA0750.1	ZBTB7A	More than 3 adjacent zinc fingers
MA0750.2	ZBTB7A	More than 3 adjacent zinc fingers
MA0750.3	ZBTB7A	More than 3 adjacent zinc fingers
MA0750.4	ZBTB7A	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:19443739, PMID:12750370

Upstream regulators (CollecTRI, top): SP1, TP53, ZBTB7A

miRNA regulators (miRDB)

174 targeting ZBTB7A, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-302E	99.96	70.74	2669

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 20.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Results suggest that FBI-1 is a cellular factor that preferentially associates with active chromatin and that can specifically stimulate Tat-activated HIV-1 transcription. (PMID:11907272)
• POZ domain of FBI1 represses transcription of ADH5. (PMID:12004059)
• found that FBI-1 binds to inverted sequence repeats downstream of the HIV-1 transcription start site (PMID:12750370)
• may contribute to adipogenesis through influencing the switch from cellular proliferation to terminal differentiation (PMID:14701838)
• Pokemon is aberrantly overexpressed in human cancers and that its expression levels predict biological behaviour and clinical outcome (PMID:15662416)
• FBI-1 enhances transcription of the NF-kappaB-responsive E-selectin gene by nuclear localization of the p65 subunit of NF-kappaB (PMID:15917220)
• The sumoylation target lysine residue at amino acid 61, which is located in the middle of the POZ-domain, is important because K61R mutation resulted in a much weaker molecular interaction with corepressors. (PMID:17595526)
• elucidate the mechanism underlying the regulation of Pokemon gene transcription, and also define a novel regulatory sequence that may be used to decrease expression of the Pokemon gene in cancer gene therapy (PMID:18355317)
• FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms. (PMID:18368381)
• Through the two-step purification, Zbtb7A protein was purified in high purity and its production reached up to as high as 18 mg/L. These results indicated that an effective procedure for expressing and purifying human Zbtb7A in P. pastoris was established (PMID:18482847)
• Pokemon had some clinical significance for prognostic evaluation of the patients with non-small cell lung cancer (PMID:18550205)
• Proto-oncogene FBI-1 (Pokemon) and SREBP-1 synergistically activate transcription of fatty-acid synthase gene (PMID:18682402)
• Proto-oncogene FBI-1 (Pokemon/ZBTB7A) represses transcription of the tumor suppressor Rb gene via binding competition with Sp1 and recruitment of co-repressors. (PMID:18801742)
• FBI-1 represses transcription of p21CIP1. FBI-1 interacted with p53 and Sp1. FBI-1 also interacted with corepressors, such as mSin3A, NCoR, and SMRT. (PMID:19244234)
• Curcumin decreases the expression of Pokemon by suppressing the binding activity of the Sp1 protein in human lung cancer cells. (PMID:19444642)
• Eukaryotic translation initiator protein 1A isoform, CCS-3, enhances the transcriptional repression of p21CIP1 by proto-oncogene FBI-1 (Pokemon/ZBTB7A). (PMID:19471103)
• This is the first report on the global mapping of ZBTB7A downstream direct targets, and these findings will be useful in understanding the roles of ZBTB7A in cellular processes. (PMID:20336405)
• ZBTB7 might be implicated in breast cancer development and may serve as a promising prognostic marker. (PMID:20394500)
• FBI-1 functions as a novel androgen receptor co-repressor in prostate cancer cells. (PMID:20812024)
• analysis of the miRNA-mediated interaction between leukemia/lymphoma-related factor (LRF) and alternative splicing factor/splicing factor 2 (ASF/SF2) affects cell senescence and apoptosis (PMID:20923760)
• knockdown of MT1-MMP abolished FBI-1-mediated cell migration and invasion. Conversely, stable knockdown of FBI-1 remarkably reduced the motility of these cells with decreased expression of MT1-MMP. (PMID:21176152)
• The expression of LRF was evaluated in benign prostate hyperplastic (BPH) and prostate cancer (PC) tissues. (PMID:21251909)
• Pokemon promotes breast cancer progression by upregulating survivin expression and may be a potential target for the treatment of this malignancy (PMID:21392388)
• FBI-1/OCZF/LRF regulates osteoclast formation and apoptosis in vivo, and may become a useful marker and target in treating disorders leading to reduced bone density, including chronic arthritis. (PMID:21590684)
• The aim of this study was to examine the regulation of LRF expression in human prostate cells. (PMID:21640721)
• The current findings indicated that FBI-1 plays an important role in HCC carcinogenesis and chemotherapy tolerance (PMID:21713761)
• siRNA of Pokemon was applied to inhibit the expression of Pokemon and NF-kappa B p65 and apoptotic rate was determined by flow cytometric analysis (PMID:21771706)
• Depletion of Pokemon inhibited proliferation of HepG(2) or induced apoptosis. (PMID:21985851)
• The activities of CDK2 and E2F4 promoters were suppressed by the modulation of Zbtb7 levels and that Zbtb7 represses promoter activities through a mechanism involving direct binding of Zbtb7 to the promoters. (PMID:22447046)
• Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. (PMID:22754333)
• The oncogene LRF is a survival factor in chondrosarcoma and contributes to tumor malignancy and drug resistance. (PMID:22847180)
• Pokemon activates the expression of both p65 and IkappaBalpha by sequence-specific binding to their promoters and plays a dual role in regulating NF-kappaB signaling. (PMID:23054188)
• Pokemon promotes cell proliferation and migration in hepatocellular carcinoma and accelerates tumor development. (PMID:23300578)
• Studies indicate that LRF regulates hematopoiesis by playing specific roles in different cell lineages. (PMID:23396304)
• ZBTB7A is a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors. (PMID:23727861)
• p38beta is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells. (PMID:23807508)
• Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cel (PMID:23874836)
• Data indicate that ZBTB7A is identified as a strong candidate for regulation of thymic insulin expression. (PMID:23911422)
• Knockdown of Pokemon protein expression inhibits hepatocellular carcinoma cell proliferation by suppression of AKT activity. (PMID:23924858)
• The mRNA expression level of Pokemon in colorectal adenocarcinoma was significantly higher than that in adjacent tumor specimens. The positive expression ratio of Pokemon protein in colorectal cancer was significantly higher than in the adjacent tissues. (PMID:24175766)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zbtb7a	ENSMUSG00000035011
rattus_norvegicus	Zbtb7a	ENSRNOG00000020161
drosophila_melanogaster	klu	FBGN0013469
drosophila_melanogaster	CG4318	FBGN0030455
caenorhabditis_elegans	klu-2	WBGENE00022592

Paralogs (4): ZNF740 (ENSG00000139651), ZNF367 (ENSG00000165244), ZBTB5 (ENSG00000168795), ZBTB43 (ENSG00000169155)

Protein

Protein identifiers

Zinc finger and BTB domain-containing protein 7A — O95365 (reviewed: O95365)

Alternative names: Factor binding IST protein 1, Factor that binds to inducer of short transcripts protein 1, HIV-1 1st-binding protein 1, Leukemia/lymphoma-related factor, POZ and Krueppel erythroid myeloid ontogenic factor, TTF-I-interacting peptide 21, Zinc finger protein 857A

All UniProt accessions (1): O95365

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation. Directly and specifically binds to the consensus sequence 5’-[GA][CA]GACCCCCCCCC-3’ and represses transcription both by regulating the organization of chromatin and through the direct recruitment of transcription factors to gene regulatory regions. Negatively regulates SMAD4 transcriptional activity in the TGF-beta signaling pathway through these two mechanisms. That is, recruits the chromatin regulator HDAC1 to the SMAD4-DNA complex and in parallel prevents the recruitment of the transcriptional activators CREBBP and EP300. Collaborates with transcription factors like RELA to modify the accessibility of gene transcription regulatory regions to secondary transcription factors. Also directly interacts with transcription factors like SP1 to prevent their binding to DNA. Functions as an androgen receptor/AR transcriptional corepressor by recruiting NCOR1 and NCOR2 to the androgen response elements/ARE on target genes. Thereby, negatively regulates androgen receptor signaling and androgen-induced cell proliferation. Involved in the switch between fetal and adult globin expression during erythroid cells maturation. Through its interaction with the NuRD complex regulates chromatin at the fetal globin genes to repress their transcription. Specifically represses the transcription of the tumor suppressor ARF isoform from the CDKN2A gene. Efficiently abrogates E2F1-dependent CDKN2A transactivation. Regulates chondrogenesis through the transcriptional repression of specific genes via a mechanism that also requires histone deacetylation. Regulates cell proliferation through the transcriptional regulation of genes involved in glycolysis. Involved in adipogenesis through the regulation of genes involved in adipocyte differentiation. Plays a key role in the differentiation of lymphoid progenitors into B and T lineages. Promotes differentiation towards the B lineage by inhibiting the T-cell instructive Notch signaling pathway through the specific transcriptional repression of Notch downstream target genes. Also regulates osteoclast differentiation. May also play a role, independently of its transcriptional activity, in double-strand break repair via classical non-homologous end joining/cNHEJ. Recruited to double-strand break sites on damage DNA, interacts with the DNA-dependent protein kinase complex and directly regulates its stability and activity in DNA repair. May also modulate the splicing activity of KHDRBS1 toward BCL2L1 in a mechanism which is histone deacetylase-dependent and thereby negatively regulates the pro-apoptotic effect of KHDRBS1.

Subunit / interactions. Homodimer. Interacts with BCL6. Interacts with RELA; involved in the control by RELA of the accessibility of target gene promoters. Interacts with AR (via NR LBD domain); the interaction is direct and androgen-dependent. Interacts with NCOR1. Interacts with NCOR2. Interacts with SMAD4; the interaction is direct and stimulated by TGFB1. Interacts with HDAC1. Interacts with SP1; ZBTB7A prevents the binding to GC-rich motifs in promoters and represses the transcriptional activity of SP1. Interacts with the DNA-dependent protein kinase complex/DNA-PKc. Interacts with KHDRBS1; negatively regulates KHDRBS1 splicing activity.

Subcellular location. Nucleus.

Tissue specificity. Widely expressed. In normal thymus, expressed in medullary epithelial cells and Hassle’s corpuscles (at protein level). In tonsil, expressed in squamous epithelium and germinal center lymphocytes (at protein level). Up-regulated in a subset of lymphomas, as well as in a subset of breast, lung, colon, prostate and bladder carcinomas (at protein level). Expressed in adipose tissues.

Post-translational modifications. Sumoylated. Undergoes sumoylation with SUMO1 that may regulate its transcriptional activity.

Disease relevance. Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MNDLFH) [MIM:619769] An autosomal dominant disease characterized by pharyngeal lymphoid hypertrophy, with adenoid overgrowth, sleep apnea, macrocephaly without structural brain abnormalities, and impaired intellectual development. An increased fraction of fetal hemoglobin has been observed in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The BTB domain mediates the interaction with the androgen receptor/AR and HDAC1. Also mediates the interaction with SP1.

RefSeq proteins (2): NP_001304919, NP_056982* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR050457	ZnFinger_BTB_dom_contain	Family

Pfam: PF00096, PF00651

UniProt features (101 total): mutagenesis site 40, helix 15, strand 11, modified residue 6, sequence variant 6, region of interest 5, turn 5, compositionally biased region 4, zinc finger region 4, cross-link 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
2IF5	X-RAY DIFFRACTION	2
2NN2	X-RAY DIFFRACTION	2.1
8H9H	X-RAY DIFFRACTION	2.2
7N5W	X-RAY DIFFRACTION	2.24
7EYI	X-RAY DIFFRACTION	2.4
8E3D	X-RAY DIFFRACTION	2.62
7N5S	X-RAY DIFFRACTION	2.86
7N5U	X-RAY DIFFRACTION	2.86
7N5T	X-RAY DIFFRACTION	2.9
8E3E	X-RAY DIFFRACTION	2.99
7N5V	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95365-F1	57.05	0.00

Functional residue map

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

Post-translational modifications (8): 337, 341, 511, 525, 526, 549, 436, 539

Mutagenesis-validated functional residues (40):

Position	Phenotype
14	no effect on transcription repressor activity. no effect on nuclear localization.
22	no effect on transcription repressor activity. no effect on nuclear localization.
49	increased proteasomal degradation. no effect on nuclear localization.
60	no effect on transcription repressor activity. no effect on nuclear localization.
61	loss of sumoylation with sumo1. may decrease interaction with transcriptional corepressors.
78	no effect on transcription repressor activity. no effect on nuclear localization.
112	no effect on transcription repressor activity. no effect on nuclear localization.
184	decreased transcription repressor activity. no effect on nuclear localization.
322	decreased transcription repressor activity. no effect on nuclear localization.
326	no effect on transcription repressor activity. no effect on nuclear localization.
354	no effect on sumoylation with sumo1. no effect on promoter binding.
357	no effect on transcription repressor activity. no effect on nuclear localization.
371	no effect on sumoylation with sumo1. no effect on promoter binding.
377	no effect on transcription repressor activity. no effect on nuclear localization.
379	no effect on sumoylation with sumo1. decreased transcription repression activity. no effect on promoter binding.
383	no effect on sumoylation with sumo1. no effect on promoter binding.
387	decreased transcription repressor activity. no effect on nuclear localization.
391	no effect on transcription repressor activity. no effect on nuclear localization.
396	no effect on sumoylation with sumo1. decreased transcription repression activity. no effect on promoter binding.
399	decreased transcription repressor activity, dominant negative effect. increased glycolysis and cell proliferation, domin
402	decreased transcription repressor activity. acts as a dominant negative. no effect on nuclear localization.
403	decreased transcription repressor activity. no effect on nuclear localization.
404	decreased transcription repressor activity. acts as a dominant negative. no effect on nuclear localization.
406	decreased transcription repressor activity. no effect on nuclear localization.
409	decreased transcription repressor activity. no effect on nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 439 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, WANG_CLIM2_TARGETS_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, CREBP1_Q2, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (21): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of alternative mRNA splicing, via spliceosome (GO:0000381), regulation of glycolytic process (GO:0006110), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), B cell differentiation (GO:0030183), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), protein localization to nucleus (GO:0034504), regulation of apoptotic process (GO:0042981), erythrocyte maturation (GO:0043249), fat cell differentiation (GO:0045444), negative regulation of Notch signaling pathway (GO:0045746), negative regulation of DNA-templated transcription (GO:0045892), obsolete regulation of DNA-binding transcription factor activity (GO:0051090), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), negative regulation of androgen receptor signaling pathway (GO:0060766), double-strand break repair via classical nonhomologous end joining (GO:0097680), regulation of transcription regulatory region DNA binding (GO:2000677), cell differentiation (GO:0030154)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription corepressor binding (GO:0001222), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), histone acetyltransferase binding (GO:0035035), SMAD binding (GO:0046332), nuclear androgen receptor binding (GO:0050681), DNA-binding transcription factor binding (GO:0140297), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), site of double-strand break (GO:0035861), DNA-dependent protein kinase complex (GO:0070418)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
glycolytic process	1
regulation of purine nucleotide catabolic process	1
regulation of generation of precursor metabolites and energy	1
regulation of carbohydrate catabolic process	1
regulation of ATP metabolic process	1
cellular component organization	1
chromatin organization	1
gene expression	1
RNA biosynthetic process	1
lymphocyte differentiation	1
B cell activation	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
protein localization to organelle	1
apoptotic process	1
regulation of programmed cell death	1
cell maturation	1
erythrocyte development	1
cell differentiation	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
androgen receptor signaling pathway	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of androgen receptor signaling pathway	1
double-strand break repair via nonhomologous end joining	1
regulation of DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1

Protein interactions and networks

STRING

1488 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZBTB7A	HDAC1	Q13547	806
ZBTB7A	SIN3A	Q96ST3	599
ZBTB7A	HEY1	Q9Y5J3	597
ZBTB7A	VPREB1	P12018	563
ZBTB7A	RUNX1	Q01196	554
ZBTB7A	MYC	P01106	552
ZBTB7A	SOX9	P48436	525
ZBTB7A	SREBF1	P36956	510
ZBTB7A	A0A0J9YYA3	A0A0J9YYA3	509
ZBTB7A	EGR1	P18146	508
ZBTB7A	NCOR1	O75376	473
ZBTB7A	BCL6	P41182	470
ZBTB7A	ZBTB32	Q9Y2Y4	468
ZBTB7A	GATA1	P15976	455
ZBTB7A	YY1	P25490	444

IntAct

43 interactions, top by confidence:

A	B	Type	Score
KHDRBS1	ZBTB7A	psi-mi:“MI:0915”(physical association)	0.650
ZBTB7A	KHDRBS1	psi-mi:“MI:0403”(colocalization)	0.650
ZBTB7A	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.650
GATAD2B	MTA2	psi-mi:“MI:0914”(association)	0.640
ZBTB7A	GATAD2B	psi-mi:“MI:0915”(physical association)	0.570
ZBTB7A	HOMEZ	psi-mi:“MI:0915”(physical association)	0.560
HOMEZ	ZBTB7A	psi-mi:“MI:0915”(physical association)	0.560
HDAC1	ZBTB7A	psi-mi:“MI:0915”(physical association)	0.560
ZBTB7A	CHD3	psi-mi:“MI:0915”(physical association)	0.510
ZBTB7A	CHD8	psi-mi:“MI:0915”(physical association)	0.510
ZBTB7A	BAZ1A	psi-mi:“MI:0915”(physical association)	0.510
ZBTB7A	ZBTB5	psi-mi:“MI:0915”(physical association)	0.370
ZBTB7A	ZBTB22	psi-mi:“MI:0915”(physical association)	0.370
ZBTB7A	ZBTB45	psi-mi:“MI:0915”(physical association)	0.370
ZBTB7A	SRCAP	psi-mi:“MI:0915”(physical association)	0.370
	ZBTB7A	psi-mi:“MI:0915”(physical association)	0.370
ZBTB7A	ZMYND8	psi-mi:“MI:0915”(physical association)	0.370
ZBTB7A	MTA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (206): HOMEZ (Two-hybrid), ZBTB7A (Two-hybrid), ZBTB7A (Reconstituted Complex), ZBTB7A (Affinity Capture-Western), KHDRBS1 (Affinity Capture-Western), KHDRBS1 (Reconstituted Complex), ZBTB7A (Biochemical Activity), ETS1 (Affinity Capture-Western), TP53 (Affinity Capture-Western), ZBTB7A (Affinity Capture-Western), ZBTB7A (Affinity Capture-Western), ZBTB7A (Reconstituted Complex), SMAD4 (Reconstituted Complex), HDAC1 (Affinity Capture-Western), ZBTB7A (Two-hybrid)

ESM2 similar proteins: A0PJY2, A1YPR0, A2A935, B0K011, B0X9H6, B7ZRU9, O13089, O15090, O15156, O75626, O88939, O93567, O95365, P14404, P25932, P41183, P56260, Q03112, Q08DS3, Q0IHB8, Q1L8W0, Q2VWH6, Q32NK7, Q3T135, Q5XJQ7, Q60636, Q64321, Q6AY34, Q6DBW0, Q6F2E4, Q802Y8, Q8I7Z8, Q8K083, Q8N9L1, Q8NAP8, Q8TBJ5, Q8VCZ7, Q8VDL9, Q98T94, Q99PV8

Diamond homologs: A0A1B8YAB1, A1YPR0, B0WWP2, B1H285, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, C9JR72, D3Z8N4, E0CZ16, G3X9X1, O15062, O88939, O93567, O95365, P28575, P41182, P41183, Q08CL3, Q08DK3, Q13105, Q16RL8, Q2M0J9, Q3UQV5, Q52KB5, Q5EXX3, Q5R7B8, Q5RDY3, Q5TC79, Q5ZI33, Q5ZKD9, Q5ZM39, Q60821

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ZBTB7A	“down-regulates quantity by repression”	CDKN2A	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 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
Interaction of NuRD complexes with transcription factors	5	37.3×	9e-06
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	5	34.6×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	9	23.4×	2e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	10
Uncertain significance	105
Likely benign	19
Benign	0

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1342832	NM_015898.4(ZBTB7A):c.1152C>G (p.Cys384Trp)	Pathogenic
1342835	NM_015898.4(ZBTB7A):c.1588del (p.Arg530fs)	Pathogenic
1342836	NM_015898.4(ZBTB7A):c.167_168delinsTT (p.Ser56Ile)	Pathogenic
1342837	NM_015898.4(ZBTB7A):c.1108C>T (p.Gln370Ter)	Pathogenic
1693512	NM_015898.4(ZBTB7A):c.642dup (p.Asn215fs)	Pathogenic
1700180	NM_015898.4(ZBTB7A):c.1466_1496del (p.Gly489fs)	Pathogenic
1702679	NM_015898.4(ZBTB7A):c.1354G>A (p.Asp452Asn)	Pathogenic
3192187	NM_015898.4(ZBTB7A):c.522del (p.Ala175fs)	Pathogenic
3255094	NM_015898.4(ZBTB7A):c.674dup (p.Ala226fs)	Pathogenic
3359129	NM_015898.4(ZBTB7A):c.98del (p.Leu33fs)	Pathogenic
3905985	NM_015898.4(ZBTB7A):c.897del (p.Ala300fs)	Pathogenic
4635002	NM_015898.4(ZBTB7A):c.1022C>A (p.Ser341Ter)	Pathogenic
4795161	NM_015898.4(ZBTB7A):c.832G>T (p.Glu278Ter)	Pathogenic
2444215	NM_015898.4(ZBTB7A):c.522dup (p.Ala175fs)	Likely pathogenic
2571911	NM_015898.4(ZBTB7A):c.692del (p.Thr231fs)	Likely pathogenic
3573594	NM_015898.4(ZBTB7A):c.1230C>A (p.Tyr410Ter)	Likely pathogenic
3771807	NM_015898.4(ZBTB7A):c.169C>T (p.Gln57Ter)	Likely pathogenic
3983741	NM_015898.4(ZBTB7A):c.1232_1234dup (p.Cys412Ter)	Likely pathogenic
4292125	NM_015898.4(ZBTB7A):c.1497del (p.Lys500fs)	Likely pathogenic
4292749	NM_015898.4(ZBTB7A):c.1499del (p.Lys500fs)	Likely pathogenic
4532785	NM_015898.4(ZBTB7A):c.237del (p.Phe79fs)	Likely pathogenic
4687935	NM_015898.4(ZBTB7A):c.171_173dup (p.Tyr58Ter)	Likely pathogenic
4755529	NM_015898.4(ZBTB7A):c.519_528del (p.Ala175fs)	Likely pathogenic

SpliceAI

794 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4055252:A:T	acceptor_gain	1.0000
19:4055255:A:T	acceptor_gain	1.0000
19:4055256:G:GC	acceptor_gain	1.0000
19:4066678:TTACC:T	donor_loss	1.0000
19:4066679:TAC:T	donor_loss	1.0000
19:4066680:A:AC	donor_gain	1.0000
19:4066680:ACC:A	donor_loss	1.0000
19:4066681:C:CC	donor_gain	1.0000
19:4066681:C:CT	donor_loss	1.0000
19:4066681:CCTCG:C	donor_gain	1.0000
19:4048241:CTGC:C	acceptor_gain	0.9900
19:4048242:TGC:T	acceptor_gain	0.9900
19:4048243:GC:G	acceptor_gain	0.9900
19:4048244:CC:C	acceptor_gain	0.9900
19:4048245:C:CC	acceptor_gain	0.9900
19:4048245:CT:C	acceptor_loss	0.9900
19:4055246:AC:A	acceptor_gain	0.9900
19:4055247:CC:C	acceptor_gain	0.9900
19:4055248:C:CC	acceptor_gain	0.9900
19:4055248:CT:C	acceptor_loss	0.9900
19:4055249:T:G	acceptor_loss	0.9900
19:4055254:CAG:C	acceptor_gain	0.9900
19:4055256:G:C	acceptor_gain	0.9900
19:4066680:AC:A	donor_gain	0.9900
19:4066681:CC:C	donor_gain	0.9900
19:4066681:CCT:C	donor_gain	0.9900
19:4048240:CCTGC:C	acceptor_gain	0.9800
19:4048241:CTGCC:C	acceptor_gain	0.9800
19:4048242:TGCCT:T	acceptor_gain	0.9800
19:4048243:GCCTG:G	acceptor_gain	0.9800

AlphaMissense

3819 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4048055:G:C	H484Q	1.000
19:4048055:G:T	H484Q	1.000
19:4048057:G:C	H484D	1.000
19:4048082:G:C	F475L	1.000
19:4048082:G:T	F475L	1.000
19:4048083:A:C	F475C	1.000
19:4048083:A:G	F475S	1.000
19:4048084:A:G	F475L	1.000
19:4048105:A:G	C468R	1.000
19:4048111:A:C	Y466D	1.000
19:4048129:G:C	H460D	1.000
19:4048135:G:T	R458S	1.000
19:4048139:G:C	H456Q	1.000
19:4048139:G:T	H456Q	1.000
19:4048141:G:C	H456D	1.000
19:4048141:G:T	H456N	1.000
19:4048149:A:G	L453P	1.000
19:4048166:A:C	F447L	1.000
19:4048166:A:T	F447L	1.000
19:4048167:A:C	F447C	1.000
19:4048167:A:G	F447S	1.000
19:4048168:A:G	F447L	1.000
19:4048168:A:T	F447I	1.000
19:4048178:G:C	C443W	1.000
19:4048179:C:G	C443S	1.000
19:4048179:C:T	C443Y	1.000
19:4048180:A:G	C443R	1.000
19:4048180:A:T	C443S	1.000
19:4048187:G:C	C440W	1.000
19:4048188:C:G	C440S	1.000

dbSNP variants (sampled 300 via entrez): RS1000102457 (19:4058684 C>T), RS1000194530 (19:4044031 C>T), RS1000233927 (19:4054955 T>C), RS1000352683 (19:4048300 C>G,T), RS1000381452 (19:4063255 C>A,G,T), RS1000382459 (19:4067703 C>T), RS1000484177 (19:4042859 C>T), RS1000761543 (19:4064303 G>C,T), RS1000799496 (19:4046561 G>A), RS1000810293 (19:4059347 C>T), RS1000819726 (19:4048493 T>G), RS1000904143 (19:4062525 C>A,T), RS1000995791 (19:4060184 T>A,G), RS1001079436 (19:4056362 C>T), RS1001101171 (19:4049534 T>C)

Disease associations

OMIM: gene MIM:605878 | disease phenotypes: MIM:619769, MIM:616078

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin	Strong	Autosomal dominant

Mondo (4): macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MONDO:0859231), hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome (MONDO:0018749), intellectual disability, autosomal dominant 29 (MONDO:0014482), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (3): Intellectual disability-lymphoid hypertrophy-macrocephaly syndrome (Orphanet:694956), Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome (Orphanet:46532), Intellectual disability-expressive aphasia-facial dysmorphism syndrome (Orphanet:436151)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000256	Macrocephaly
HP:0000483	Astigmatism
HP:0000678	Dental crowding
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001537	Umbilical hernia
HP:0001601	Laryngomalacia
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0002020	Gastroesophageal reflux
HP:0002036	Hiatus hernia
HP:0002788	Recurrent upper respiratory tract infections
HP:0003577	Congenital onset
HP:0006335	Persistence of primary teeth
HP:0006532	Recurrent pneumonia
HP:0010535	Sleep apnea
HP:0011220	Prominent forehead
HP:0011904	Persistence of hemoglobin F
HP:0011968	Feeding difficulties
HP:0025352	Typically de novo
HP:0025502	Overweight
HP:0040261	Increased size of nasopharyngeal adenoids

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST004146_28	Chronic lymphocytic leukemia	5.000000e-08
GCST004601_184	Red blood cell count	6.000000e-29
GCST004602_258	Mean corpuscular volume	5.000000e-45
GCST004630_53	Mean corpuscular hemoglobin	2.000000e-39
GCST006268_230	Reaction time	6.000000e-10
GCST006268_487	Reaction time	2.000000e-10
GCST007269_172	Pulse pressure	1.000000e-10
GCST010988_13	Adult body size	4.000000e-15
GCST90002390_512	Mean corpuscular hemoglobin	5.000000e-84
GCST90002392_52	Mean corpuscular volume	1.000000e-98
GCST90002396_9	Mean reticulocyte volume	6.000000e-43
GCST90002397_399	Mean spheric corpuscular volume	1.000000e-77
GCST90002403_272	Red blood cell count	4.000000e-65

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0008393	reaction time measurement
EFO:0005763	pulse pressure measurement
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5069375 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Zinc finger TFs

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
BMS-986470	Binding	14.0	pEC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	increases expression, decreases expression, increases abundance	3
bisphenol A	affects cotreatment, increases methylation, decreases expression, decreases methylation	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Arsenic	increases abundance, increases expression, affects methylation, affects cotreatment	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
cupric chloride	increases expression	1
coumarin	decreases phosphorylation	1
mithramycin A	increases expression, decreases reaction	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
Resveratrol	decreases expression, decreases reaction, increases reaction, affects binding, increases expression (+2 more)	1
Temozolomide	decreases expression, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Fluorouracil	decreases expression, affects response to substance	1
Manganese	affects cotreatment, increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5059508	Binding	Proteomics fold change data (SUDHL4 cells, 1h)	Data for DCP probe CCT369260

Cellosaurus cell lines

7 cell lines: 3 embryonic stem cell, 2 cancer cell line, 1 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7GC	GZHMCi007-A	Induced pluripotent stem cell	Male
CVCL_A8B1	SEES3-1V human ZBTB7A, clone1	Embryonic stem cell	Male
CVCL_A8B2	SEES3-1V human ZBTB7A, clone2	Embryonic stem cell	Male
CVCL_A8B3	SEES3-1V human ZBTB7A, clone3	Embryonic stem cell	Male
CVCL_C7Z6	HAP1 ZBTB7A (-) 1	Cancer cell line	Male
CVCL_C7Z7	HAP1 ZBTB7A (-) 2	Cancer cell line	Male
CVCL_HD01	HEK293 eGFP-ZBTB7A	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder