Chronic hepatitis B virus (HBV) persistence relies on the chromatin plasticity of covalently closed circular DNA (cccDNA), a viral minichromosome resistant to current therapies. Using proximity labeling (TurboID-dCas9), ChIP-seq and DNA pull-down assays, we identified SMARCC2-a BAF scaffolding subunit-bound to cccDNA enhancer-promoter regions (EnhⅠ/XP, CP/EnhII), where it sustains nucleosome-depleted regions (NDRs) and recruits RNA polymerase II. Genetic or pharmacological BAF inhibition compacted cccDNA chromatin, reduced histone acetylation (AcH3/AcH4), and enhanced SMC5/6-mediated silencing to suppress transcription, with the BAF ATPase inhibitor FHT-2344 reducing serum HBV DNA by 50% (P <.05) and intrahepatic HBV RNA by 70% (P <.01) without cccDNA loss, indicating epigenetic silencing. Mechanistically, BAF maintains NDRs by counteracting nucleosome retention and recruiting host transcription factors such as HNF4α. This work concludes that BAF safeguards cccDNA chromatin plasticity to enable viral persistence, and targeting BAF (e.g. FHT-2344) epigenetically silences cccDNA, offering a novel strategy for functional cure.
Huang et al. (Thu,) studied this question.