Direct recruitment of RNA Polymerase II by NANOG to activated target genes

Cell identity relies upon transcription factors (TFs). The concentration of the TF NANOG determines the efficiency of maintenance of mouse embryonic stem cell (ESC) identity. However, the mechanisms by which NANOG acts are not fully understood. Models of mammalian transcription generally propose that TFs bind DNA and connect to the transcriptional machinery indirectly via intermediary proteins. Accordingly, examples of direct contact between cell-type specific TFs and RNA synthesis enzymes in mammalian cells remain elusive. Here we show that NANOG directly contacts RNA Polymerase II (RNAPII) via aromatic residues within the low complexity domains of both proteins. NANOG can localize RNAPII to a specific DNA site, with RNAPII enhancing NANOG DNA affinity. The NANOG-RNAPII complex is dissociated by the transcriptional pause-release enzyme, CDK9. Inhibition of CDK9 enhances NANOG chromatin binding, while induction of NANOG localizes RNAPII to specific NANOG chromatin sites. Induced RNAPII localization is selective for targets activated by NANOG. A NANOG mutant that retains DNA, but not RNAPII binding, cannot stimulate RNAPII localization to chromatin, shows an impaired transcriptional response and does not drive LIF-independent ESC self-renewal. These results identify a novel, regulatable interaction between a cell-type specific TF and RNAPII that can change transcription and alter cell fate.