ZNF143 binds DNA and stimulates transcription initiation to activate and repress direct target genes (ATAC-seq)

Transcription factors bind to sequence motifs and act as activators or repressors. Transcription factors interface with a constellation of accessory cofactors to regulate distinct mechanistic steps to regulate transcription. We rapidly degraded the essential and ubiquitously expressed transcription factor ZNF143 to determine its function in the transcription cycle. ZNF143 facilitates RNA Polymerase initiation and activates gene expression. ZNF143 binds the promoter of nearly all its activated target genes. Paradoxically, ZNF143 binds near the site of genic transcription initiation to directly repress a subset of genes. Although ZNF143 stimulates initiation at ZNF143-repressed genes (i.e. those that increase expression upon ZNF143 depletion), the molecular context of binding leads to cis repression. ZNF143 competes with other more efficient activators for promoter access, physically occludes transcription initiation sites, and acts as a molecular roadblock to RNA Polymerase to repress genes in cis. The term "context specific" is often invoked to describe transcription factors that have both activation and repression functions. Here, we define the context and molecular mechanisms of ZNF143-mediated cis activation and repression.