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

RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance 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 previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation. The examined ZFPs show widespread sequence-specific RNA binding and preferentially bind proximal to transcription start sites. Additionally, several ZFPs associate with 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 DNA/RNA-associated protein that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation. [Display omitted] •Discovered RNA-binding ZFPs and characterized their substrates•Identified ZFPs that regulate splicing, stability, and polyadenylation•ZNF277 is a multi-functional RBP with thousands of binding targets•ZNF473 is a DNA/RNA-associated protein that regulates cell cycle genes Gosztyla et al. identify the RNAs bound by zinc-finger proteins and demonstrate the roles of zinc-finger proteins in the RNA life cycle. They highlight two zinc-finger proteins of particular interest: ZNF277, a multi-functional RNA-binding protein, and ZNF473, a DNA/RNA-associated protein that regulates cell cycle genes.