Integrated multi-omics analysis of zinc finger proteins uncovers roles in RNA regulation [RNA-seq]

RNA interactome studies have revealed that hundreds of zinc finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), despite being annotated as DNA-interacting transcription factors. The RNA substrates of ZFPs and the functional significance of their potential roles as DNA- and RNA-binding proteins (DRBPs) remain largely uncharacterized. Here we present a systematic multi-omics analysis of the DNA and RNA binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc finger families. We show that multiple ZFPs are novel regulators of RNA splicing, polyadenylation, or stability. The examined ZFPs show widespread sequence-specific RNA binding ability and preferentially bind proximal to transcription start sites. Additionally, several ZFPs are DRBPs that bind their targets at both the DNA and RNA levels. We highlight ZNF277, a C2H2 ZFP that binds thousands of RNA targets and acts as a multi-functional RBP. We also show that ZNF473 is a DRBP that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation, shedding light on a large class of under-studied RBPs.