ZNF91 is a KRAB zinc finger transcription factor that functions as a sequence-specific repressor of SINE-VNTR-Alu (SVA) retrotransposons. ZNF91 recognizes and binds SVA sequences, particularly the VNTR region, and recruits the corepressor complex containing TRIM28/KAP1 to establish repressive chr19 through H3K9me3 and DNA methylation modifications 12. Genome-wide deletion of ZNF91 in human embryonic stem cells results in increased SVA transcriptional activity and adoption of cis-regulatory properties by young SVAs, with mild upregulation of proximal genes 1. Additionally, ZNF91 specifically binds G4-forming DNA sequences within SVAs and can bind the FCGR2B promoter, functioning as a transcriptional repressor 34. ZNF91 has disease relevance in X-linked dystonia-parkinsonism (XDP), where it represses an SVA insertion in the TAF1 gene; ZNF91 expression decreases with age, potentially explaining XDP's progressive neurodegeneration 42. Variants in ZNF91 associate with benign paroxysmal positional vertigo in genome-wide studies 5, and ZNF91 has been identified as a significantly mutated gene in colorectal cancer 6. These findings suggest ZNF91 represents an innate epigenetic defense mechanism against transposon-mediated genome dysregulation.