Affinage

ZNF644

Zinc finger protein 644 · UniProt Q9H582

Length
1327 aa
Mass
149.6 kDa
Annotated
2026-06-11
9 papers in source corpus 3 papers cited in narrative 4 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF644 is a zinc finger transcription factor that operates as a DNA-targeting subunit of the G9a/GLP histone H3K9 methyltransferase complex, coupling sequence-specific chromatin recognition to repressive H3K9 mono- and dimethylation (PMID:25789554). Within the complex, ZNF644 engages the transcription activation domain of G9a specifically—distinct from its paralog WIZ, which binds GLP—establishing parallel, non-redundant targeting routes for the two enzymatic subunits (PMID:25789554). Through its multiple zinc finger motifs, ZNF644 recognizes consensus DNA sequences and thereby recruits the methyltransferase complex to chromatin to silence target loci (PMID:25789554). Beyond this chromatin role, ZNF644 supports cell cycle progression and survival: its depletion arrests cells in G1/G2, reduces proliferation, and increases apoptosis (PMID:30021720). The gene is expressed in human retina and retinal pigment epithelium, and loss-of-function mutations co-segregate with autosomal dominant high myopia (PMID:21695231).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2011 Low

    Before any molecular function was known, it was unclear whether ZNF644 had a role in the eye; linking it to a disease and tissue established it as a candidate ocular gene.

    Evidence Exome and Sanger sequencing in high-myopia families with expression analysis in retina/RPE

    PMID:21695231

    Open questions at the time
    • No molecular mechanism connecting ZNF644 to myopia demonstrated
    • Genetic co-segregation does not establish causal biochemical pathway
    • Ocular cell-type-specific function not defined
  2. 2015 High

    The biochemical function of ZNF644 was unknown; identifying it as a core G9a/GLP subunit that recognizes DNA and targets the complex to chromatin defined it as the sequence-specific recruiter for H3K9 methylation-mediated repression.

    Evidence Unbiased affinity purification, reciprocal co-IP, chromatin targeting and H3K9 methylation assays

    PMID:25789554

    Open questions at the time
    • Genome-wide repertoire of ZNF644 target loci not mapped
    • DNA consensus specificity per zinc finger not resolved
    • Link between this chromatin role and the myopia phenotype not established
  3. 2015 Medium

    It was unclear how the two enzymatic subunits of the complex are independently targeted; mapping ZNF644 to the G9a activation domain and WIZ to GLP revealed parallel, subunit-specific recruitment.

    Evidence Affinity purification and co-IP interaction-domain mapping

    PMID:25789554

    Open questions at the time
    • Structural basis of the ZNF644-G9a interaction not determined
    • Functional consequence of losing one targeting route versus the other not tested
    • Single-study domain mapping
  4. 2018 Medium

    Whether ZNF644 has cellular roles beyond chromatin repression was open; showing it is miR-362-regulated and required for cell cycle progression and survival in Sertoli cells extended its role to proliferation control.

    Evidence Luciferase 3'UTR reporter, miR-362 mimic/inhibitor, flow cytometry, proliferation assays in porcine Sertoli cells

    PMID:30021720

    Open questions at the time
    • Demonstrated in porcine, not human, cells
    • Mechanistic link between cell-cycle role and H3K9 methyltransferase function not established
    • Downstream cell-cycle targets unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZNF644's chromatin-targeting function mechanistically produces the high-myopia phenotype, and which target loci it represses in retinal tissue, remains unresolved.
  • No genome-wide target map in retinal/RPE cells
  • No animal model linking H3K9 methylation defects to myopia
  • Disease mutations not functionally connected to complex assembly or methylation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-4839726 Chromatin organization 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
EHMT1EHMT2WIZ
Complex memberships
G9a/GLP histone methyltransferase complex

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ZNF644 is a core subunit of the G9a/GLP histone methyltransferase complex; it interacts with the transcription activation domain of G9a and contains multiple zinc finger motifs that recognize consensus DNA sequences, thereby targeting G9a to chromatin and mediating G9a/GLP complex-dependent H3K9 mono- and dimethylation and gene repression. Unbiased protein affinity purification, co-immunoprecipitation, chromatin targeting assays, H3K9 methylation assays eLife High 25789554
2015 ZNF644 interacts specifically with the transcription activation domain of G9a (not GLP), while the paralog WIZ interacts with GLP, establishing distinct targeting mechanisms within the same complex. Protein affinity purification and co-immunoprecipitation mapping of interaction domains eLife Medium 25789554
2018 ZNF644 is targeted by miR-362 in porcine immature Sertoli cells; miR-362 binds the 3'UTR of ZNF644 mRNA and suppresses its expression. Knockdown of ZNF644 arrests cells in G1/G2 phases, inhibits proliferation, and enhances apoptosis, indicating ZNF644 is required for normal cell cycle progression and survival in Sertoli cells. Dual luciferase reporter assay (3'UTR), miR-362 mimic/inhibitor transfection, flow cytometry (cell cycle/apoptosis), CCK8 and EdU proliferation assays, qRT-PCR Yi chuan = Hereditas Medium 30021720
2011 ZNF644 is expressed in human retina and retinal pigment epithelium (RPE), consistent with a role in ocular development; loss-of-function mutations in ZNF644 co-segregate with autosomal dominant high myopia in affected families. Exome sequencing, Sanger sequencing validation, expression analysis in retinal/RPE tissue PLoS genetics Low 21695231

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Exome sequencing identifies ZNF644 mutations in high myopia. PLoS genetics 161 21695231
2014 Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Investigative ophthalmology & visual science 94 25525168
2015 The zinc finger proteins ZNF644 and WIZ regulate the G9a/GLP complex for gene repression. eLife 52 25789554
2012 Study of a US cohort supports the role of ZNF644 and high-grade myopia susceptibility. Molecular vision 28 22539872
2014 New ZNF644 mutations identified in patients with high myopia. Molecular vision 14 24991186
2022 Downregulation of circ-ZNF644 alleviates LPS-induced HK2 cell injury via miR-335-5p/HIPK1 axis. Environmental toxicology 9 36052886
2021 Mutational screening of AGRN, SLC39A5, SCO2, P4HA2, BSG, ZNF644, and CPSF1 in a Chinese cohort of 103 patients with nonsyndromic high myopia. Molecular vision 8 35002215
2014 [Association of ZNF644, GRM6 and CTNND2 genes polymorphisms with high myopia]. Zhonghua yi xue za zhi 4 25142846
2018 [miR-362 regulates the proliferation and apoptosis of porcine immature Sertoli cells through targeting the ZNF644 gene]. Yi chuan = Hereditas 2 30021720

Missed literature

Know a paper Affinage missed for ZNF644? Flag it for the maintainers and the community.

No submissions yet.