ZNF274 is a KRAB-containing zinc finger protein that functions as a transcriptional repressor with specialized roles in genome organization and epigenetic silencing 1. The protein contains five C2H2-type zinc-finger motifs and KRAB domains that exhibit transcription repressor activity, with nucleolar localization mediated by its third and fourth zinc fingers 1. Mechanistically, ZNF274 recruits chr19-modifying complexes to silence genes. It specifically binds the 3' ends of zinc-finger coding genes and recruits SETDB1 and TRIM28/KAP1 to establish H3K9me3 repressive marks 2. Additionally, ZNF274 anchors lineage-specific gene clusters—including protocadherin and other KZFP-encoding genes—within nucleolus-associated domains (NADs), where its SCAN domain facilitates compartmentalization into perinucleolar repressive hubs 3. ZNF274 also regulates cell cycle progression by controlling expression timing of hundreds of clustered genes 4. Clinically, ZNF274 is relevant to Prader-Willi syndrome (PWS), where it represses the maternal SNORD116 cluster through H3K9me3 deposition 5. ZNF274 inactivation or binding site deletion reactivates silenced maternal transcripts 67, suggesting therapeutic potential. ZNF274 binding sites are also enriched at NAFLD-associated methylation sites 8, indicating broader metabolic disease relevance.