ZBTB16

Summary

ZBTB16 (zinc finger and BTB domain containing 16, HGNC:12930) is a protein-coding gene on chromosome 11q23.2, encoding Zinc finger and BTB domain-containing protein 16 (Q05516). Acts as a transcriptional repressor.

This gene is a member of the Krueppel C2H2-type zinc-finger protein family and encodes a zinc finger transcription factor that contains nine Kruppel-type zinc finger domains at the carboxyl terminus. This protein is located in the nucleus, is involved in cell cycle progression, and interacts with a histone deacetylase. Specific instances of aberrant gene rearrangement at this locus have been associated with acute promyelocytic leukemia (APL). Alternate transcriptional splice variants have been characterized.

Source: NCBI Gene 7704 — RefSeq curated summary.

At a glance

• Gene–disease (curated): skeletal defects, genital hypoplasia, and intellectual disability (Moderate, GenCC)
• GWAS associations: 58
• Clinical variants (ClinVar): 107 total
• Phenotypes (HPO): 36
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Transcription factor: yes — 55 downstream targets (CollecTRI)
• MANE Select transcript: NM_006006

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12930
Approved symbol	ZBTB16
Name	zinc finger and BTB domain containing 16
Location	11q23.2
Locus type	gene with protein product
Status	Approved
Aliases	PLZF
Ensembl gene	ENSG00000109906
Ensembl biotype	protein_coding
OMIM	176797
Entrez	7704

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 45 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000335953, ENST00000392996, ENST00000535379, ENST00000535509, ENST00000535700, ENST00000539918, ENST00000541602, ENST00000544220, ENST00000545851, ENST00000682218, ENST00000682278, ENST00000682697, ENST00000682810, ENST00000682971, ENST00000683006, ENST00000683233, ENST00000683318, ENST00000683554, ENST00000684295, ENST00000684612, ENST00000865543, ENST00000865544, ENST00000865545, ENST00000865546, ENST00000865547, ENST00000865548, ENST00000865549, ENST00000865550, ENST00000865551, ENST00000865552, ENST00000865553, ENST00000865554, ENST00000865555, ENST00000865556, ENST00000865557, ENST00000865558, ENST00000865559, ENST00000865560, ENST00000865561, ENST00000865562, ENST00000959056, ENST00000959057, ENST00000959058, ENST00000959059, ENST00000959060, ENST00000959061, ENST00000959062, ENST00000959063, ENST00000959064, ENST00000959065, ENST00000959066, ENST00000959067, ENST00000959068, ENST00000959069

RefSeq mRNA: 5 — MANE Select: NM_006006 NM_001018011, NM_001354750, NM_001354751, NM_001354752, NM_006006

CCDS: CCDS8367, CCDS91597

Canonical transcript exons

ENST00000335953 — 7 exons

Exon	Start	End
ENSE00001344383	114059711	114059882
ENSE00001513888	114250326	114256765
ENSE00003532715	114063211	114064568
ENSE00003533854	114247198	114247365
ENSE00003574983	114242167	114242337
ENSE00003606532	114156337	114156434
ENSE00003667676	114186952	114187038

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 98.62.

FANTOM5 (CAGE): breadth broad, TPM avg 14.6466 / max 453.7683, expressed in 852 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116771	8.1494	726
116768	3.5072	694
116770	1.9246	448
116772	0.5352	261
116769	0.2912	118
116773	0.1398	58
116774	0.0992	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of hip	UBERON:0001554	98.62	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.44	gold quality
tibialis anterior	UBERON:0001385	98.34	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.23	gold quality
pericardium	UBERON:0002407	98.01	gold quality
saphenous vein	UBERON:0007318	97.90	gold quality
upper leg skin	UBERON:0004262	97.73	gold quality
deltoid	UBERON:0001476	97.69	gold quality
biceps brachii	UBERON:0001507	97.65	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.60	gold quality
nipple	UBERON:0002030	97.59	gold quality
body of tongue	UBERON:0011876	97.56	gold quality
synovial joint	UBERON:0002217	97.27	gold quality
parietal lobe	UBERON:0001872	97.06	gold quality
gastrocnemius	UBERON:0001388	97.02	gold quality
skeletal muscle tissue	UBERON:0001134	97.00	gold quality
postcentral gyrus	UBERON:0002581	97.00	gold quality
right lung	UBERON:0002167	96.91	gold quality
muscle of leg	UBERON:0001383	96.90	gold quality
muscle organ	UBERON:0001630	96.84	gold quality
middle temporal gyrus	UBERON:0002771	96.74	gold quality
mucosa of stomach	UBERON:0001199	96.59	gold quality
oocyte	CL:0000023	96.54	gold quality
calcaneal tendon	UBERON:0003701	96.52	gold quality
quadriceps femoris	UBERON:0001377	96.43	gold quality
urethra	UBERON:0000057	96.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.29	gold quality
vastus lateralis	UBERON:0001379	96.19	gold quality
sural nerve	UBERON:0015488	96.18	gold quality
popliteal artery	UBERON:0002250	96.08	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	1447.76
E-CURD-112	yes	812.00
E-MTAB-10287	yes	56.59
E-CURD-122	yes	40.55
E-HCAD-6	yes	25.08
E-ANND-3	yes	23.55
E-HCAD-1	yes	18.92
E-CURD-88	yes	17.47
E-HCAD-10	yes	9.89
E-MTAB-9067	yes	9.63
E-MTAB-6678	yes	5.36
E-GEOD-99795	no	118.21
E-MTAB-8060	no	44.24

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

55 targets.

Target	Regulation
ADAMTS7
AGTR2
ANGPT2
ATP6V1B2
ATXN1
BCL2	Repression
BGLAP	Repression
BID	Repression
BMP2
CCNA2	Repression
CD34
CDC6
CDKN1A	Repression
CDKN2A
CDKN2B
CEBPA	Unknown
CEL
COL1A1	Activation
CRABP1	Activation
CXCR4	Activation
FGF2	Repression
FGFR1
FGFR3
GATA4
GFI1	Unknown
GP1BA
GP9
GSR
HOXB2
ID2	Unknown

Upstream regulators (CollecTRI, top): AR, GFI1, ID2, KDM6A, MECOM, RARA, ZBTB16

miRNA regulators (miRDB)

3 targeting ZBTB16, 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-627-3P	99.90	71.42	3316
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-1237-3P	98.55	67.65	1423

Literature-anchored findings (GeneRIF, showing 40)

• two critical hits for promyelocytic leukemia (PMID:11106752)
• PLZF/RARalpha also binds the HD-NCR through the PLZF, which seems to be crucial for the t-RA resistance of t(11;17) APL patients (PMID:11920278)
• can interact with GATA-2 and can modify GATA-2 transactivation capacity (PMID:11964310)
• evidence of a functional interaction between the promyelocytic leukemia zinc finger protein (PLZF) and DRAL/FHL2 (PMID:12145280)
• PLZF plays a significant stimulatory role in megakaryocytic development, seemingly mediated in part by induction of TpoR expression at transcriptional level. (PMID:12242665)
• Hoxb2 is a direct target for regulation by PLZF in the developing CNS and suggest that deregulation of Hox gene expression may contribute to APL pathogenesis. (PMID:12802276)
• gene expression regulation in human endometrial stromal cells and myometrial smooth muscle cells (PMID:12970399)
• PLZF colocalizes with SUMO-1 in the nucleus; lysine 242 in the RD2 domain of human PLZF was identified as the sumoylation site (PMID:14527952)
• PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. (PMID:14645547)
• An inactive mutant of PLZF abolishes expression of p85 alpha PI3K followed by enhanced p70(S6) kinase. (PMID:14657020)
• a suppressor role in solid tumors (PMID:15077196)
• data indicate that recruitment of HDAC4 is necessary for PLZF-mediated repression in both normal and leukaemic cells (PMID:15467736)
• PLZF plays important roles in early osteoblastic differentiation as an upstream regulator of CBFA1 (PMID:15623533)
• Histone acetyltransferase activity of p300 is required for transcriptional repression by PZLF. (PMID:15964811)
• Androgen-independent cell line DU145 cells lack PLZF gene expression, resulting in the upregulation of Pbx1 and HoxC8 expression. The Pbx1-HoxC8 heterocomplex may lead to androgen-independent growth in prostate cancer. (PMID:16637071)
• These data suggest the existence of a mechanism that regulates ERK signaling via the C-terminus of ATP7B and the ATP7B-interacting hepatocytic PLZF. (PMID:16676348)
• potential tumor suppressor activity of CCS-3 may be mediated by its interaction with PLZF. (PMID:16828757)
• existence of a novel signal transduction pathway involving the ligand renin, renin receptor, and the transcription factor PLZF (PMID:17082479)
• The collapsin response mediator protein 1 and the promyelocytic leukemia zinc finger protein interact with UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). (PMID:17118363)
• TIMP1 regulates cell proliferation by interacting with the ninth zinc finger domain of PZLF. (PMID:17340613)
• Expression of PLZF in corneal endothelial cells is closely related to formation of cell-cell contacts, and PLZF may play role in suppressing their proliferation. (PMID:17515885)
• PLZF upregulates apoptosis-inducer TP53INP1, ID1, and ID3 genes, and downregulates the apoptosis-inhibitor TERT gene (PMID:17537403)
• PLZF mRNA was expressed in HCECs in vivo and in completely confluent HCECs but not in subconfluent HCECs in vitro. (PMID:17881917)
• supports an active role for PLZF and RARalpha-PLZF in leukemogenesis, identifies up-regulation of CRABPI (PMID:18000064)
• Activated Goalpha interacted directly with PLZF, and enhanced its function as a transcriptional and cell growth suppressor. (PMID:18262754)
• PLZF post-translational modification is controlled by intracellular ROS, and the biological function of PLZF is regulated by sumoylation and ubiquitination. (PMID:18348865)
• PLZF negatively regulates the expression of miR-221 and miR-222 (PMID:18417445)
• observations suggest that PLZF is a negative regulator of ENaC in renal epithelial cells and might be part of a negative feedback loop that limits aldosterone’s stimulatory effects on sodium reabsorption. (PMID:18448589)
• Data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation. (PMID:18568019)
• Our findings that PLZF is a key regulator of skeletal and male germline development. (PMID:18611983)
• study suggests that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development (PMID:18703361)
• Increased expression of the tumor suppressor PLZF in malignant melanomas is associated with long-term patient survival. (PMID:18771349)
• Data indicate a new mechanism of regulation of c-kit expression that involves a transcriptional control by PLZF in CD34(+) cells. (PMID:19421145)
• The 2 PLZF mutants are oncogenic, because they function as dominant negatives of wild-type PLZF, enhancing Myc phosphorylation and increasing Myc transcriptional and oncogenic activity. (PMID:19444914)
• PLZF/RARA expression leads to recruitment of the Polycomb-repressive complex 2 (PRC2) Polycomb group (PcG) complex to RA response elements (PMID:19451220)
• one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression (PMID:19648967)
• During homeostasis, PLZF restricts proliferation and differentiation of human cord blood-derived myeloid progenitors to maintain a balance between the progenitor and mature cell compartments (PMID:19723763)
• The role of PLZF in human hematopoiesis was studied. (PMID:19796243)
• Data show that PLZF-RARalpha binds to a region of the c-MYC promoter, suggesting that PLZF-RARalpha may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. (PMID:19855079)
• Data indicate that deletions of PLZF are a common occurrence in MM and that downregulation of PLZF may contribute to MM pathogenesis by promoting cell survival. (PMID:20010871)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zbtb16a	ENSDARG00000007184
mus_musculus	Zbtb16	ENSMUSG00000066687
rattus_norvegicus	Zbtb16	ENSRNOG00000029980

Paralogs (36): ZBTB32 (ENSG00000011590), SNAI2 (ENSG00000019549), PRDM1 (ENSG00000057657), PRDM6 (ENSG00000061455), ZNF76 (ENSG00000065029), PATZ1 (ENSG00000100105), MAZ (ENSG00000103495), ZNF451 (ENSG00000112200), ZBTB45 (ENSG00000119574), ZNF410 (ENSG00000119725), SNAI1 (ENSG00000124216), ZNF384 (ENSG00000126746), ZBTB1 (ENSG00000126804), VEZF1 (ENSG00000136451), PRDM14 (ENSG00000147596), ZNF276 (ENSG00000158805), ZNF362 (ENSG00000160094), ZNF653 (ENSG00000161914), ZNF281 (ENSG00000162702), ZNF148 (ENSG00000163848), ZNF143 (ENSG00000166478), HIC2 (ENSG00000169635), PRDM10 (ENSG00000170325), ZNF296 (ENSG00000170684), ZNF692 (ENSG00000171163), ZNF575 (ENSG00000176472), HIC1 (ENSG00000177374), ZBTB18 (ENSG00000179456), ZBTB42 (ENSG00000179627), ZBTB20 (ENSG00000181722), ZBTB7C (ENSG00000184828), SNAI3 (ENSG00000185669), ZFP91 (ENSG00000186660), MTF1 (ENSG00000188786), SCRT2 (ENSG00000215397), SCRT1 (ENSG00000261678)

Protein

Protein identifiers

Zinc finger and BTB domain-containing protein 16 — Q05516 (reviewed: Q05516)

Alternative names: Promyelocytic leukemia zinc finger protein, Zinc finger protein 145, Zinc finger protein PLZF

All UniProt accessions (7): Q05516, A0A024R3C6, A0A0S2Z4J5, A0A804HIC1, A0A804HJ45, F5H6C3, H0YGW2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional repressor. Transcriptional repression may be mediated through recruitment of histone deacetylases to target promoters. May play a role in myeloid maturation and in the development and/or maintenance of other differentiated tissues. Probable substrate-recognition component of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Subunit / interactions. Binds EPN1. Interacts with ZBTB32 and CUL3. Interacts with ATP7B. Interacts with transcriptional corepressor RUNX1T1 (via its N-terminus); the interaction increases the transcription repression activity of ZBTB16. Interacts (via C2H2-type zinc finger domains 1 and 2) with RNF112.

Subcellular location. Nucleus. Nuclear body.

Tissue specificity. Within the hematopoietic system, PLZF is expressed in bone marrow, early myeloid cell lines and peripheral blood mononuclear cells. Also expressed in the ovary, and at lower levels, in the kidney and lung.

Disease relevance. Skeletal defects, genital hypoplasia, and impaired intellectual development (SGYMR) [MIM:612447] A disorder characterized by intellectual disability, craniofacial dysmorphism, microcephaly and short stature. Additional features include absence of the thumbs, hypoplasia of the radii and ulnae, additional vertebrae and ribs, retarded bone age and genital hypoplasia. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving ZBTB16 may be a cause of acute promyelocytic leukemia (APL). Translocation t(11;17)(q32;q21) with RARA.

Induction. By retinoic acid.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q05516-1	PLZFB	yes
Q05516-2	PLZFA

RefSeq proteins (5): NP_001018011, NP_001341679, NP_001341680, NP_001341681, NP_005997* (*=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

Pfam: PF00096, PF00651, PF13912

UniProt features (39 total): zinc finger region 9, helix 8, modified residue 6, strand 4, region of interest 3, compositionally biased region 2, chain 1, domain 1, site 1, splice variant 1, sequence variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1BUO	X-RAY DIFFRACTION	1.9
1CS3	X-RAY DIFFRACTION	2
8YTH	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05516-F1	56.02	0.04

Functional residue map

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

Catalytic / active sites (1): 394–395 (breakpoint for translocation to form plzf-rar-alpha oncogene)

Post-translational modifications (6): 76, 184, 197, 256, 282, 628

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 0 (showing top):

GO Biological Process (39): negative regulation of transcription by RNA polymerase II (GO:0000122), mesonephros development (GO:0001823), tolerance induction in gut-associated lymphoid tissue (GO:0002394), regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), central nervous system development (GO:0007417), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), embryonic pattern specification (GO:0009880), anterior/posterior pattern specification (GO:0009952), protein ubiquitination (GO:0016567), hemopoiesis (GO:0030097), myeloid cell differentiation (GO:0030099), positive regulation of chondrocyte differentiation (GO:0032332), protein localization to nucleus (GO:0034504), embryonic hindlimb morphogenesis (GO:0035116), forelimb morphogenesis (GO:0035136), embryonic digit morphogenesis (GO:0042733), positive regulation of apoptotic process (GO:0043065), ossification involved in bone maturation (GO:0043931), regulatory T cell differentiation (GO:0045066), positive regulation of fat cell differentiation (GO:0045600), negative regulation of myeloid cell differentiation (GO:0045638), positive regulation of ossification (GO:0045778), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), male germ-line stem cell asymmetric division (GO:0048133), positive regulation of NK T cell differentiation (GO:0051138), cartilage development (GO:0051216), positive regulation of cartilage development (GO:0061036), skeletal system development (GO:0001501), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), positive regulation of macromolecule biosynthetic process (GO:0010557), hindlimb morphogenesis (GO:0035137), regulation of cell differentiation (GO:0045595), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of multicellular organismal process (GO:0051240), regulation of multicellular organismal development (GO:2000026)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), transcription corepressor binding (GO:0001222), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), transcription coregulator activity (GO:0003712), zinc ion binding (GO:0008270), protein domain specific binding (GO:0019904), type 2 angiotensin receptor binding (GO:0031703), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), double-stranded DNA binding (GO:0003690), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): chromatin (GO:0000785), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), cytosol (GO:0005829), nuclear body (GO:0016604), PML body (GO:0016605), nuclear speck (GO:0016607), transcription repressor complex (GO:0017053), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
embryonic limb morphogenesis	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription regulator activity	2
protein binding	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
kidney development	1
immune response in gut-associated lymphoid tissue	1
tolerance induction in mucosal-associated lymphoid tissue	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
nervous system development	1
system development	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
pattern specification process	1
embryo development	1
regionalization	1
protein modification by small protein conjugation	1
cell development	1
hemopoiesis	1
cell differentiation	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
positive regulation of cell differentiation	1
positive regulation of cartilage development	1
protein localization to organelle	1
hindlimb morphogenesis	1
limb morphogenesis	1
embryonic morphogenesis	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1

Protein interactions and networks

STRING

2888 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZBTB16	RARA	P10276	960
ZBTB16	BMI1	P35226	888
ZBTB16	R4GMX3	R4GMX3	887
ZBTB16	NCOR1	O75376	879
ZBTB16	CUL3	Q13618	876
ZBTB16	NCOR2	Q9Y618	868
ZBTB16	HDAC4	P56524	843
ZBTB16	NUMA1	Q14980	816
ZBTB16	STRA8	Q7Z7C7	814
ZBTB16	NANOS2	P60321	769
ZBTB16	NPM1	P06748	736
ZBTB16	GATA3	P23771	729
ZBTB16	GFRA1	P56159	729
ZBTB16	PRAM1	Q96QH2	721
ZBTB16	RUNX1T1	Q06455	702

IntAct

303 interactions, top by confidence:

A	B	Type	Score
ZBTB16	ZBTB16	psi-mi:“MI:0915”(physical association)	0.840
ZBTB16	LAMTOR5	psi-mi:“MI:0915”(physical association)	0.830
LAMTOR5	ZBTB16	psi-mi:“MI:0915”(physical association)	0.830
KRT40	ZBTB16	psi-mi:“MI:0915”(physical association)	0.810
ZBTB16	KRT40	psi-mi:“MI:0915”(physical association)	0.810
ZBTB16	GOLGA2	psi-mi:“MI:0915”(physical association)	0.790
GOLGA2	ZBTB16	psi-mi:“MI:0915”(physical association)	0.790
ZBTB16	TRAF2	psi-mi:“MI:0915”(physical association)	0.740
TRIM54	ZBTB16	psi-mi:“MI:0915”(physical association)	0.720
ZBTB16	TRIM54	psi-mi:“MI:0915”(physical association)	0.720
ZBTB16	TRAF1	psi-mi:“MI:0915”(physical association)	0.700
ZBTB16	COG6	psi-mi:“MI:0915”(physical association)	0.700
TRAF1	ZBTB16	psi-mi:“MI:0915”(physical association)	0.700
COG6	ZBTB16	psi-mi:“MI:0915”(physical association)	0.700

BioGRID (323): ZBTB16 (Two-hybrid), ZBTB16 (Affinity Capture-Western), ZBTB16 (Affinity Capture-Western), ZBTB16 (Two-hybrid), ZBTB16 (Two-hybrid), LAMTOR5 (Two-hybrid), TRIM54 (Two-hybrid), SH2D4A (Two-hybrid), KRT40 (Two-hybrid), ZBTB16 (Affinity Capture-Western), Rnf112 (Affinity Capture-Western), Rnf112 (Co-localization), ZBTB16 (Affinity Capture-MS), SPOP (Two-hybrid), ZBTB16 (Two-hybrid)

ESM2 similar proteins: A0A1D5NS60, A0JN76, A1L2U9, B1WAZ8, E9Q3T6, O15060, O15062, O35260, O93567, P41182, P41183, Q05516, Q0IH98, Q0IJ29, Q0P4X6, Q0V8G8, Q1L8W0, Q3B725, Q3B7N9, Q3SWU4, Q5EAC5, Q5EXX3, Q5R5N5, Q5SW75, Q5ZM39, Q6DDV0, Q6NRK3, Q6NRM8, Q6ZSB9, Q7TQG0, Q7TS63, Q7TSZ8, Q7ZWZ4, Q801P1, Q80X44, Q86VK4, Q8BKX7, Q8BXX2, Q8CII0, Q8NAP3

Diamond homologs: A1YGK1, A2T7E6, E1B932, Q05516, Q53G59, Q5U374, Q6NRH0, Q802Y8, Q8BZM0, Q8R2H4, Q9JKD9, Q9Y2Y4, A0JN76, A1YPR0, B1WBU4, E0CZ16, F1LZ52, F1LZF0, F1MBP6, O14682, O15062, O15156, O15209, O35260, O35709, O43829, O88939, O93567, O95198, O95365, P28575, P41182, P41183, P97302, P97303, Q08376, Q08BL9, Q08DK3, Q0IJ29, Q0P4X6

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
CDK2	down-regulates	ZBTB16	phosphorylation
ZBTB16	“down-regulates quantity by repression”	miR-146a	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	ZBTB16	“transcriptional regulation”
ZBTB16	“up-regulates quantity by expression”	RSAD2	“transcriptional regulation”
GSK3B	“up-regulates activity”	ZBTB16	phosphorylation
ZBTB16	“form complex”	ZBTB16/ZBTB32	binding
FLT3	“down-regulates activity”	ZBTB16
ZBTB16	down-regulates	Proliferation
ZBTB16	up-regulates	Apoptosis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 59 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.

GO biological processes:

GO term	Partners	Fold	FDR
Golgi organization	5	13.1×	5e-03
positive regulation of canonical NF-kappaB signal transduction	6	8.6×	7e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — ESCC, PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	26
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3321 predictions. Top by Δscore:

Variant	Effect	Δscore
11:114063209:A:AG	acceptor_gain	1.0000
11:114063210:G:GG	acceptor_gain	1.0000
11:114063210:GCCTC:G	acceptor_gain	1.0000
11:114156332:TACA:T	acceptor_loss	1.0000
11:114156334:CA:C	acceptor_loss	1.0000
11:114156335:AG:A	acceptor_gain	1.0000
11:114156335:AGGA:A	acceptor_loss	1.0000
11:114156336:GG:G	acceptor_gain	1.0000
11:114156336:GGA:G	acceptor_gain	1.0000
11:114156336:GGAA:G	acceptor_gain	1.0000
11:114156432:CAGG:C	donor_loss	1.0000
11:114156433:AGGT:A	donor_loss	1.0000
11:114156434:GG:G	donor_loss	1.0000
11:114156435:G:GC	donor_loss	1.0000
11:114156436:T:G	donor_loss	1.0000
11:114186950:AGC:A	acceptor_gain	1.0000
11:114186950:AGCG:A	acceptor_gain	1.0000
11:114186951:GCG:G	acceptor_gain	1.0000
11:114186951:GCGG:G	acceptor_gain	1.0000
11:114242164:CAGG:C	acceptor_loss	1.0000
11:114242165:A:AG	acceptor_gain	1.0000
11:114242165:A:C	acceptor_loss	1.0000
11:114242166:G:GA	acceptor_gain	1.0000
11:114242166:GGCA:G	acceptor_gain	1.0000
11:114242275:G:GG	donor_gain	1.0000
11:114247192:CCACA:C	acceptor_loss	1.0000
11:114247193:CACAG:C	acceptor_loss	1.0000
11:114247195:CAG:C	acceptor_loss	1.0000
11:114247196:A:AG	acceptor_gain	1.0000
11:114247196:AG:A	acceptor_gain	1.0000

AlphaMissense

4456 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:114247215:T:C	C548R	1.000
11:114247224:T:C	C551R	1.000
11:114247225:G:A	C551Y	1.000
11:114247226:T:G	C551W	1.000
11:114247236:T:C	F555L	1.000
11:114247237:T:C	F555S	1.000
11:114247238:C:A	F555L	1.000
11:114247238:C:G	F555L	1.000
11:114247255:T:C	L561P	1.000
11:114247263:C:G	H564D	1.000
11:114247275:C:G	H568D	1.000
11:114247277:C:A	H568Q	1.000
11:114247277:C:G	H568Q	1.000
11:114247299:T:C	C576R	1.000
11:114247320:T:C	F583L	1.000
11:114247321:T:C	F583S	1.000
11:114247322:C:A	F583L	1.000
11:114247322:C:G	F583L	1.000
11:114247339:T:C	L589P	1.000
11:114250343:T:C	C604R	1.000
11:114250427:T:C	C632R	1.000
11:114063551:T:C	L84P	0.999
11:114063616:G:C	A106P	0.999
11:114156389:T:C	F441L	0.999
11:114156391:C:A	F441L	0.999
11:114156391:C:G	F441L	0.999
11:114242187:T:C	C492R	0.999
11:114242189:T:G	C492W	0.999
11:114242196:T:C	C495R	0.999
11:114242208:T:C	F499L	0.999

dbSNP variants (sampled 300 via entrez): RS1000004625 (11:114172678 G>A), RS1000012776 (11:114091997 C>A,T), RS1000015733 (11:114156266 C>A,T), RS1000016842 (11:114080482 A>T), RS1000021442 (11:114195593 G>A), RS1000048030 (11:114109496 G>A), RS1000071195 (11:114234089 G>A), RS1000072112 (11:114193892 C>A), RS1000073370 (11:114184139 C>T), RS1000077510 (11:114109705 G>A,C), RS1000092734 (11:114069939 G>A), RS1000098261 (11:114113008 C>A), RS1000108067 (11:114235232 G>A,C), RS1000109137 (11:114182369 C>A,G), RS1000147323 (11:114124194 T>A)

Disease associations

OMIM: gene MIM:176797 | disease phenotypes: MIM:612447

GenCC curated gene-disease

Disease	Classification	Inheritance
skeletal defects, genital hypoplasia, and intellectual disability	Moderate	Autosomal recessive

Mondo (1): skeletal defects, genital hypoplasia, and intellectual disability (MONDO:0012909)

Orphanet (0):

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000212	Gingival overgrowth
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001324	Muscle weakness
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0002321	Vertigo
HP:0002653	Bone pain
HP:0002716	Lymphadenopathy
HP:0002875	Exertional dyspnea
HP:0005521	Disseminated intravascular coagulation
HP:0010280	Stomatitis
HP:0011900	Hypofibrinogenemia
HP:0012378	Fatigue
HP:0025420	Diffuse alveolar hemorrhage
HP:0030140	Oral cavity bleeding
HP:0030955	Addictive alcohol use

GWAS associations

58 associations (top):

Study	Trait	p-value
GCST000245_9	Conduct disorder (maternal expressed emotions interaction)	9.000000e-06
GCST002875_44	Diisocyanate-induced asthma	2.000000e-07
GCST003227_9	Non-glioblastoma glioma	6.000000e-11
GCST004251_6	Paneth cell defects in Crohn’s disease	3.000000e-06
GCST004348_7	Non-glioblastoma glioma	5.000000e-12
GCST004599_101	Mean platelet volume	8.000000e-18
GCST004599_102	Mean platelet volume	3.000000e-13
GCST004603_64	Platelet count	6.000000e-21
GCST004603_65	Platelet count	9.000000e-13
GCST004607_132	Plateletcrit	1.000000e-09
GCST004608_171	Granulocyte percentage of myeloid white cells	8.000000e-22
GCST004609_187	Monocyte percentage of white cells	9.000000e-10
GCST004609_25	Monocyte percentage of white cells	2.000000e-20
GCST004610_121	White blood cell count	3.000000e-10
GCST004610_122	White blood cell count	3.000000e-10
GCST004613_26	Sum neutrophil eosinophil counts	2.000000e-12
GCST004613_27	Sum neutrophil eosinophil counts	2.000000e-12
GCST004614_2	Granulocyte count	1.000000e-12
GCST004614_3	Granulocyte count	2.000000e-12
GCST004620_124	Sum basophil neutrophil counts	9.000000e-13
GCST004620_125	Sum basophil neutrophil counts	1.000000e-12
GCST004626_111	Myeloid white cell count	2.000000e-10
GCST004626_112	Myeloid white cell count	6.000000e-12
GCST004629_97	Neutrophil count	1.000000e-12
GCST004629_98	Neutrophil count	9.000000e-13
GCST005273_6	Polycystic ovary syndrome	1.000000e-06
GCST005803_7	Corneal astigmatism	4.000000e-06
GCST007089_10	Polycystic ovary syndrome	2.000000e-10
GCST007576_143	Chronotype	1.000000e-10
GCST010736_9	Urinary albumin-to-creatinine ratio	1.000000e-08

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0008342	parental emotion expression measurmement
EFO:0006995	response to diisocyanate
EFO:0007963	abnormal paneth cell measurement
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:1002040	Corneal astigmatism
EFO:0008328	chronotype measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0005670	smoking initiation
EFO:0004527	mean corpuscular hemoglobin
EFO:0005091	monocyte count
EFO:0010701	mean reticulocyte volume
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567306	Skeletal Defects, Genital Hypoplasia, And Mental Retardation (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105726 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	6
bisphenol A	affects expression, decreases expression, affects cotreatment	3
trichostatin A	affects cotreatment, decreases expression	3
Tobacco Smoke Pollution	decreases expression, increases methylation	3
Tretinoin	decreases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression, affects cotreatment	3
sodium arsenite	affects methylation, decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
bisphenol S	decreases expression, affects cotreatment, increases methylation	2
Panobinostat	affects cotreatment, decreases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Ethanol	affects expression, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
Dexamethasone	increases expression, affects cotreatment, affects expression, decreases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Progesterone	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
GSK-J4	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4015788	Binding	Inhibition of GAL4 DNA binding domain fused PLZF BTB domain (unknown origin) expressed in HEK 293T/17 cells after 24 hrs by Bright-Glo luciferase cell reporter assay	Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8RZ	Abcam HCT 116 ZBTB16 KO	Cancer cell line	Male
CVCL_B9CK	Abcam MCF-7 ZBTB16 KO	Cancer cell line	Female
CVCL_B9UI	Abcam A-549 ZBTB16 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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