BANP opens chromatin and activates CpG island regulated genes [SLAM-Seq]

In mammalian genomes, the vast majority of RNA polymerase II initiation events take place at CpG island promoters. Despite their relevance our understanding of their regulation remains limited. Here we identify Banp as the long sought-after TF that binds the orphan CGCG element in CpG islands by combining single-molecule footprinting with interaction proteomics. We show that Banp drives activity of CpG islands that control essential metabolic genes in the mouse and human genome. Banp binding is strongly repelled by DNA methylation of its motif in vitro and in vivo, which restricts most binding to CpG islands and accounts for its absence at aberrantly methylated CpG islands in cancer cells. Upon binding to an unmethylated motif, Banp opens chromatin and positions nucleosomes. These findings expand our understanding of CpG island gene regulation and put forth a model whereby CpG islands rely for their activity on methylation sensitive TFs capable of opening and organizing chromatin. Overall design: SLAM-seq in mouse ESCs. Wt (s4U untreated and treated). dTag untreated and dTag treated for 1h, 2h, 4h, 6h and 20h (all s4U treated). All conditions in triplicates, except dTag untreated (duplicates).