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The transcription factor Forkhead box A2 (FOXA2) is a master regulator of endoderm development and of mature endoderm-derived organs, including the liver, and tight control of its expression and activity is paramount for the proper execution of developmental and homeostatic gene programs. In this study, we investigated the biological significance of FOXA2 alternative transcripts and uncovered an unexpected and previously unrecognized role for FOXA2 in transcriptional repression, particularly in the context of viral gene regulation. We show that FOXA2 alternative transcripts arise from distinct transcription start sites, rather than alternative splicing, and that the resulting protein isoforms are functionally equivalent, indicating that alternative promoter usage primarily serves to fine-tune FOXA2 expression, rather than to diversify protein function.

Unexpectedly, despite its established role as a pioneer transcription factor and transcriptional activator, FOXA2 exhibited robust repressive activity in differentiated liver cells. FOXA2 over-expression led to widespread repression of endogenous genes, including autorepression of the FOXA2 gene itself, and, notably, to dramatic suppression of viral regulatory elements. Among these, the SV40 early promoter—an essential driver of viral replication and cellular transformation—was strongly repressed by FOXA2. Targeted mutagenesis revealed that FOXA2 DNA binding is sufficient to drive repression of the SV40 early promoter, and that this repression depends critically on intact NF-κB response elements. Repression was most pronounced on regulatory elements whose activity is highly dependent on NF-κB, identifying NF-κB–driven promoters as a key target of FOXA2 repressive activity.

Mechanistically, EMSA and immunoblot analyses indicate that FOXA2 does not repress viral promoters through direct competition with NF-κB for DNA binding. Instead, FOXA2 expression was associated with reduced NF-κB protein abundance, at least in part through proteasome-dependent degradation, revealing a novel indirect mechanism by which FOXA2 constrains NF-κB–dependent transcription. Given that many viruses, including SV40 and HIV-1, rely heavily on NF-κB activity to drive early gene expression and the transition from latency to productive infection, our findings suggest that FOXA2 may function as a host-derived, context-dependent restriction factor that limits viral gene expression in differentiated tissues.