ZNF683

Summary

ZNF683 (zinc finger protein 683, HGNC:28495) is a protein-coding gene on chromosome 1p36.11, encoding Tissue-resident T-cell transcription regulator protein ZNF683 (Q8IZ20). Transcription factor that mediates a transcriptional program in various innate and adaptive immune tissue-resident lymphocyte T-cell types such as tissue-resident memory T (Trm), natural killer (trNK) and natural killer T (NKT) cells and negatively regulates gene expression of p….

Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in T cell receptor signaling pathway; cellular response to ionomycin; and regulation of gene expression. Predicted to be located in nucleus.

Source: NCBI Gene 257101 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 94 total
• MANE Select transcript: NM_001114759

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28495
Approved symbol	ZNF683
Name	zinc finger protein 683
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	MGC33414, Hobit
Ensembl gene	ENSG00000176083
Ensembl biotype	protein_coding
OMIM	616775
Entrez	257101

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000349618, ENST00000403843, ENST00000416125, ENST00000423508, ENST00000436292, ENST00000451801, ENST00000453132, ENST00000454975, ENST00000455900, ENST00000897146, ENST00000897147, ENST00000897148, ENST00000897149

RefSeq mRNA: 3 — MANE Select: NM_001114759 NM_001114759, NM_001307925, NM_173574

CCDS: CCDS279, CCDS76126

Canonical transcript exons

ENST00000349618 — 6 exons

Exon	Start	End
ENSE00001230976	26367593	26367797
ENSE00001337229	26368458	26368585
ENSE00001549666	26361634	26362022
ENSE00001672510	26363026	26363154
ENSE00001743360	26364532	26365226
ENSE00003901552	26372669	26372750

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 94.37.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0156 / max 197.0256, expressed in 97 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11174	0.6246	81
11173	0.2803	43
11172	0.0432	17
11175	0.0426	3
11176	0.0165	3
201419	0.0044	3
11177	0.0040	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	94.37	gold quality
left testis	UBERON:0004533	94.33	gold quality
right testis	UBERON:0004534	94.09	gold quality
granulocyte	CL:0000094	93.09	gold quality
testis	UBERON:0000473	91.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.07	gold quality
parotid gland	UBERON:0001831	82.98	silver quality
vena cava	UBERON:0004087	82.65	gold quality
heart right ventricle	UBERON:0002080	81.98	silver quality
upper arm skin	UBERON:0004263	81.86	gold quality
left ventricle myocardium	UBERON:0006566	80.44	gold quality
cardiac muscle of right atrium	UBERON:0003379	80.39	gold quality
pancreatic ductal cell	CL:0002079	78.57	silver quality
adult organism	UBERON:0007023	78.38	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.01	silver quality
trabecular bone tissue	UBERON:0002483	77.90	silver quality
body of tongue	UBERON:0011876	77.24	silver quality
lateral nuclear group of thalamus	UBERON:0002736	77.02	silver quality
pons	UBERON:0000988	76.37	silver quality
lateral globus pallidus	UBERON:0002476	76.30	silver quality
epithelial cell of pancreas	CL:0000083	76.15	gold quality
cerebellar vermis	UBERON:0004720	75.78	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	75.44	silver quality
layer of synovial tissue	UBERON:0007616	74.62	gold quality
substantia nigra pars reticulata	UBERON:0001966	74.47	silver quality
blood	UBERON:0000178	74.22	gold quality
right uterine tube	UBERON:0001302	74.11	gold quality
substantia nigra pars compacta	UBERON:0001965	73.72	silver quality
pylorus	UBERON:0001166	73.69	silver quality
cardia of stomach	UBERON:0001162	73.30	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8911	yes	591.56
E-ANND-3	no	2.18

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA2522.1	ZNF683	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:39605320

Literature-anchored findings (GeneRIF, showing 7)

• These data implicate Hobit as a novel transcriptional regulator in quiescent human effector-type CD8(+) T cells that regulates their immediate effector functions. (PMID:26179882)
• Hobit’s function in human T cells is highly adapted to lifelong, periodic challenges with varying, physiological doses of pathogens. (PMID:26440905)
• Transcription factor Hobit identifies a subset of NK cells in Human livers that express a distinct set of adhesion molecules and chemokine receptors consistent with tissue residency. These data suggest that Hobit is involved in regulating tissue-residency of human intrahepatic CD56bright NK cells in a subset of NK cells in inflamed livers. (PMID:28751776)
• These findings suggest that Blimp-1 initiates cytotoxic effector function and that Hobit maintains cytotoxicity in a deployment-ready modus in tissue-resident memory CD8 T cells. (PMID:30051906)
• Transcription Factor ZNF683 Inhibits SIV/HIV Replication through Regulating IFNgamma Secretion of CD8+ T Cells. (PMID:35458449)
• Single-cell transcriptome profiling reveals the key role of ZNF683 in natural killer cell exhaustion in multiple myeloma. (PMID:36245253)
• Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer. (PMID:36869093)

Cross-species orthologs

0 orthologs

Paralogs (28): ZNF280C (ENSG00000056277), ZBTB25 (ENSG00000089775), PRDM13 (ENSG00000112238), BCL6 (ENSG00000113916), FEZF1 (ENSG00000128610), ZBTB46 (ENSG00000130584), PRDM12 (ENSG00000130711), ZNF280D (ENSG00000137871), NACC2 (ENSG00000148411), FEZF2 (ENSG00000153266), ZBTB7B (ENSG00000160685), NACC1 (ENSG00000160877), BCL6B (ENSG00000161940), GFI1 (ENSG00000162676), GFI1B (ENSG00000165702), ZBTB49 (ENSG00000168826), ZNF280A (ENSG00000169548), ZNF581 (ENSG00000171425), ZNF524 (ENSG00000171443), ZBTB26 (ENSG00000171448), ZBTB21 (ENSG00000173276), ZBTB33 (ENSG00000177485), ZBTB3 (ENSG00000185670), ZBTB6 (ENSG00000186130), ZBTB14 (ENSG00000198081), ZBTB12 (ENSG00000204366), ZNF580 (ENSG00000213015), ZNF280B (ENSG00000275004)

Protein

Protein identifiers

Tissue-resident T-cell transcription regulator protein ZNF683 — Q8IZ20 (reviewed: Q8IZ20)

Alternative names: Homolog of Blimp-1 in T-cell, Zinc finger protein 683

All UniProt accessions (7): A0A0A0MSJ7, A0A0A0MT21, Q8IZ20, Q5T142, Q5T145, X1WI31, X1WI32

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that mediates a transcriptional program in various innate and adaptive immune tissue-resident lymphocyte T-cell types such as tissue-resident memory T (Trm), natural killer (trNK) and natural killer T (NKT) cells and negatively regulates gene expression of proteins that promote the egress of tissue-resident T-cell populations from non-lymphoid organs. Plays a role in the development, retention and long-term establishment of adaptive and innate tissue-resident lymphocyte T cell types in non-lymphoid organs, such as the skin and gut, but also in other nonbarrier tissues like liver and kidney, and therefore may provide immediate immunological protection against reactivating infections or viral reinfection. Also plays a role in the differentiation of both thymic and peripheral NKT cells. Negatively regulates the accumulation of interferon-gamma (IFN-gamma) in NKT cells at steady state or after antigenic stimulation. Positively regulates granzyme B production in NKT cells after innate stimulation. Associates with the transcriptional repressor PRDM1/BLIMP1 to chromatin at gene promoter regions. Lacks transcriptional repressor activity. Binds to DNA within promoter regions of the transcriptional repressor PRDM1/BLIMP1 target sites. Unable to regulate interferon-gamma (IFN-gamma) production in cytomegalovirus (CMV)-infected effector CD8(+) T-cells. Transcriptional repressor that binds to DNA within promoter regions of the transcriptional repressor PRDM1/BLIMP1 target sites. Regulates interferon-gamma (IFN-gamma) production in cytomegalovirus (CMV)-infected effector CD8(+) T cells.

Subcellular location. Nucleus.

Tissue specificity. Expressed in terminally differentiated effector CD8(+) T-cells, but not in naive and central memory cells. Expressed in terminally differentiated natural killer (NK) cells and natural killer (NKT) T-cells (at protein level). Expressed strongly in effector-type CD8(+) T-cells and weakly in naive and memory CD8(+) T-cells. Expressed in terminally differentiated natural killer (NK) cells. Isoform 2 is strongly expressed in effector CD8(+) T and natural killer (NK) cells. Isoform 1 is expressed in effector CD8(+) T and natural killer (NK) cells. (Microbial infection) Expressed in cytomegalovirus (CMV)-infected effector CD8(+) T-cells (at protein level).

Domain organisation. The C2H2-type zinc finger are necessary for DNA-binding.

Induction. (Microbial infection) Up-regulated by cytomegalovirus (CMV) infection in long-lived effector CD8(+) T-cells.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZ20-1	1, Extra large, XL	yes
Q8IZ20-2	2, Large, L

RefSeq proteins (3): NP_001108231, NP_001294854, NP_775845 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR050331	Zinc_finger_PRDM4/PRDM1/PRDM14	Family

Pfam: PF00096

UniProt features (14 total): sequence variant 5, zinc finger region 4, region of interest 2, chain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZ20-F1	50.04	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 96 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NATURAL_KILLER_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_NATURAL_KILLER_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_TYPE_II_INTERFERON_PRODUCTION

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), adaptive immune response (GO:0002250), regulation of transcription by RNA polymerase II (GO:0006357), regulation of gene expression (GO:0010468), positive regulation of gene expression (GO:0010628), negative regulation of type II interferon production (GO:0032689), regulation of natural killer cell differentiation (GO:0032823), obsolete regulation of natural killer cell differentiation involved in immune response (GO:0032826), regulation of extrathymic T cell differentiation (GO:0033082), innate immune response (GO:0045087), T cell receptor signaling pathway (GO:0050852), regulation of NK T cell differentiation (GO:0051136), cellular response to ionomycin (GO:1904637), immune system process (GO:0002376), regulation of immune system process (GO:0002682), regulation of multicellular organismal process (GO:0051239)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
immune response	2
regulation of DNA-templated transcription	2
gene expression	2
regulation of biological process	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
regulation of macromolecule biosynthetic process	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
natural killer cell differentiation	1
regulation of natural killer cell activation	1
regulation of lymphocyte differentiation	1
extrathymic T cell differentiation	1
regulation of T cell differentiation	1
defense response to symbiont	1
antigen receptor-mediated signaling pathway	1
NK T cell differentiation	1
regulation of alpha-beta T cell differentiation	1
cellular response to ether	1
cellular response to fatty acid	1
response to ionomycin	1
biological_process	1
immune system process	1
multicellular organismal process	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
transition metal ion binding	1
chromatin binding	1
nucleic acid binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

568 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNF683	EOMES	O95936	608
ZNF683	ITGAE	P38570	607
ZNF683	ITGA1	P56199	606
ZNF683	RUNX3	Q13761	595
ZNF683	S1PR1	P21453	592
ZNF683	TBX21	Q9UL17	580
ZNF683	CD69	Q07108	577
ZNF683	KLRD1	Q13241	554
ZNF683	CXCR6	O00574	546
ZNF683	KLRK1	P26718	524
ZNF683	GZMK	P49863	513
ZNF683	PRDM1	O75626	512
ZNF683	CCR7	P32248	507
ZNF683	CD8A	P01732	507
ZNF683	CRTAM	O95727	490

IntAct

16 interactions, top by confidence:

A	B	Type	Score
CYSRT1	ZNF683	psi-mi:“MI:0915”(physical association)	0.560
ZNF683	ZNF330	psi-mi:“MI:0915”(physical association)	0.560
PRR20D	ZNF683	psi-mi:“MI:0915”(physical association)	0.560
ZNF683	RHOXF2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-2	ZNF683	psi-mi:“MI:0915”(physical association)	0.560
ZNF683	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000
ZNF330	ZNF683	psi-mi:“MI:0915”(physical association)	0.000
PRR20D	ZNF683	psi-mi:“MI:0915”(physical association)	0.000
RHOXF2	ZNF683	psi-mi:“MI:0915”(physical association)	0.000
ZNF683	KRTAP6-2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): ZNF683 (Two-hybrid), ZNF683 (Two-hybrid), KRTAP6-2 (Two-hybrid), CYSRT1 (Two-hybrid), PRR20B (Two-hybrid), PRR20A (Two-hybrid), PRR20D (Two-hybrid), PRR20C (Two-hybrid), PRR20E (Two-hybrid)

ESM2 similar proteins: A0A5F9ZHS7, A1YGK1, A2T7E6, A8MZG2, O08574, O43593, O60393, O75593, O88621, O95231, P0C1T1, P0CG20, P20428, P97609, Q04667, Q17QR5, Q2KIS6, Q2M1V0, Q2T9Q7, Q32LE6, Q497V6, Q5JUK2, Q5M844, Q5RJB0, Q5TGS1, Q61645, Q61657, Q6ZMY3, Q6ZN32, Q6ZNG2, Q7RTU1, Q8BZW2, Q8CGW9, Q8IWN7, Q8IXT2, Q8IZ20, Q8N1L9, Q8N7G0, Q8N944, Q8N9Y4

Diamond homologs: I7HJS4, O75626, Q60636, Q8IZ20, Q93560, A0A163UT06, A2AGX3, A2AJ77, A2BID7, A6QPM3, B4F6U4, E9Q3T6, E9Q8T2, P0C6Y7, P57071, Q13029, Q3UTQ7, Q3UZD5, Q5R5M1, Q5RAX9, Q63755, Q80V63, Q96EQ9, Q9CXE0, Q9GZV8, Q9H4Q4, Q9NQV5, Q9NQV6, Q9NQV7, Q9NQW5, Q9NQX0, Q9NQX1, Q9QZP2, Q9UKN5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1368 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26367591:A:AC	donor_gain	1.0000
1:26367592:C:CC	donor_gain	1.0000
1:26367592:CT:C	donor_gain	1.0000
1:26362020:CAC:C	acceptor_gain	0.9900
1:26362021:ACC:A	acceptor_loss	0.9900
1:26362022:CCT:C	acceptor_loss	0.9900
1:26362023:CTGA:C	acceptor_loss	0.9900
1:26362024:T:G	acceptor_loss	0.9900
1:26365115:C:CA	donor_gain	0.9900
1:26372667:A:AC	donor_gain	0.9900
1:26372668:C:CC	donor_gain	0.9900
1:26372668:CT:C	donor_gain	0.9900
1:26372687:T:A	donor_gain	0.9900
1:26362018:CACAC:C	acceptor_gain	0.9800
1:26363019:ATCTC:A	donor_loss	0.9800
1:26363020:TCTCA:T	donor_loss	0.9800
1:26363021:CTCA:C	donor_loss	0.9800
1:26363022:TCACC:T	donor_loss	0.9800
1:26363023:CACCG:C	donor_loss	0.9800
1:26363024:A:T	donor_loss	0.9800
1:26364527:GATA:G	donor_loss	0.9800
1:26364528:ATAC:A	donor_loss	0.9800
1:26364529:TA:T	donor_loss	0.9800
1:26364530:ACC:A	donor_loss	0.9800
1:26364531:C:CA	donor_loss	0.9800
1:26364562:G:A	donor_gain	0.9800
1:26365054:T:A	donor_gain	0.9800
1:26365120:G:A	donor_gain	0.9800
1:26365146:G:C	donor_gain	0.9800
1:26365151:T:TA	donor_gain	0.9800

AlphaMissense

3280 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26362005:G:C	F407L	0.999
1:26362005:G:T	F407L	0.999
1:26362007:A:G	F407L	0.999
1:26363075:A:G	L365P	0.999
1:26363092:G:C	F359L	0.999
1:26363092:G:T	F359L	0.999
1:26363094:A:G	F359L	0.999
1:26364553:A:C	F331L	0.999
1:26364553:A:T	F331L	0.999
1:26364555:A:G	F331L	0.999
1:26364576:A:G	C324R	0.999
1:26361921:G:C	F435L	0.998
1:26361921:G:T	F435L	0.998
1:26361923:A:G	F435L	0.998
1:26362006:A:G	F407S	0.998
1:26363067:G:C	H368D	0.998
1:26363093:A:G	F359S	0.998
1:26363104:G:C	C355W	0.998
1:26363106:A:G	C355R	0.998
1:26363115:A:G	C352R	0.998
1:26363119:G:C	F350L	0.998
1:26363119:G:T	F350L	0.998
1:26363121:A:G	F350L	0.998
1:26363147:A:G	L341P	0.998
1:26364536:A:G	L337P	0.998
1:26364565:A:C	C327W	0.998
1:26364566:C:G	C327S	0.998
1:26364566:C:T	C327Y	0.998
1:26364567:A:G	C327R	0.998
1:26364567:A:T	C327S	0.998

dbSNP variants (sampled 300 via entrez): RS1000083207 (1:26373586 C>G), RS1000148673 (1:26361615 C>T), RS1000178584 (1:26366271 G>A), RS1000357740 (1:26372420 A>G), RS1000834320 (1:26371959 C>T), RS1000992854 (1:26361170 C>A), RS1001145081 (1:26366800 C>T), RS1001252855 (1:26364467 G>C), RS1001435913 (1:26370570 C>G), RS1001643707 (1:26371004 C>T), RS1001867751 (1:26363685 T>C), RS1001926782 (1:26370032 G>A), RS1002082844 (1:26375464 C>A), RS1002719579 (1:26363533 C>T), RS1003157382 (1:26363922 T>A,C)

Disease associations

OMIM: gene MIM:616775 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
GSK-J4	decreases expression	1
butylbenzyl phthalate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
Amiodarone	increases expression	1
Testosterone	decreases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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