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

• DOI: 10.1016/j.molcel.2024.08.010
• Publication Date: 2024-09-19T15:54:27Z
• Authors: Maya L. Gosztyla; Lijun Zhan; Sara Olson; Xintao Wei; Jack Naritomi; Grady Nguyen; Lena Street; Grant A. Goda; Francisco F. Cavazos; Jonathan C. Schmok; Manya Jain; Easin Uddin Syed; Eunjeong Kwon; Wenhao Jin; Eric Kofman; Alexandra T. Tankka; Allison Li; Valerie Gonzalez; Eric Lécuyer; Daniel Dominguez; Marko Jovanovic; Brenton R. Graveley; Gene W. Yeo
• Keywords: Omics

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.