biostudies-literatureGosztyla MLNatural Sciences and Engineering Research Council of CanadaFonds de recherche du Quebec SanteNSFNIA NIH HHSNIMH NIH HHSMyotonic Dystrophy FoundationNIHChan Zuckerberg InitiativeCIHRNHGRI NIH HHSNCI NIH HHSAssociation for Women in ScienceNIGMS NIH HHSNIH HHS3826-3842.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC11633308biostudies-literatureUnknown84(19)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 Molecular cellIntegrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation.PMC11633308R35 GM142864S10 OD025052R01 HG004659U41 HG009889T32 CA067754U24 HG011735R01 HG012216R01 HG011864S10 OD026929R01 AG071869RF1 MH126719U54 CA209891U24 HG009889P41 GM103504Gonzalez VJin WCavazos FFUddin Syed EGoda GAJain MGosztyla MLOlson STankka ATDominguez DWei XKwon EYeo GWNaritomi JNguyen GLecuyer ESchmok JCStreet LJovanovic MGraveley BRKofman ELi AZhan LfalseIntegrated 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 2024-01-01T00:00:00Z2024 Oct2026-06-03T05:10:56.777Z2025-04-04T02:33:09.63ZS-EPMC116333083930372210.1016/j.molcel.2024.08.010