The N-terminus of YY1 regulates DNA and RNA binding affinity for both the zinc-fingers and an unexpected nucleic acid binding domain

Transcription factors (TFs) play central roles in dictating cellular identity and function by regulating gene expression programs. Beyond their well-folded DNA binding domains (DBDs) which recognize cognate DNA elements in the genome, TFs are enriched for intrinsically disordered regions (IDRs), which have a host of proposed functions including facilitating protein-protein interactions, aiding in binding site search, and binding RNA. Defining intrinsic regulatory properties of TFs requires further mechanistic investigation. We chose to investigate the DNA and RNA binding properties of Yin Yang 1 (YY1), a ubiquitously expressed TF directly involved in transcriptional activation, repression and genome architecture. Through systematic in vitro nucleic acid binding experiments we resolve conflicting literature defining the RNA binding interface of YY1, demonstrating that there are two RNA binding domains within YY1: its canonical 4 zinc finger DBD and a previously unannotated nucleic acid binding domain, which we term the REPO-NAB. Furthermore, we discover surprising autoinhibitory properties that the N-terminus of the protein imparts on each of these binding domains. Our results provide a new example of IDR-mediated regulation within TFs and enables future mechanistically precise functional investigations.