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.
Authors
- Francisco F. Cavazos (ORCID: https://orcid.org/0009-0000-1804-9601)
- Alexandra T. Tankka (ORCID: https://orcid.org/0000-0003-3337-5725)
- Valerie Gonzalez
- Jonathan C. Schmok (ORCID: https://orcid.org/0000-0002-5173-902X)
- Grady G. Nguyen (ORCID: https://orcid.org/0009-0005-0512-3522)
- Éric Lécuyer (ORCID: https://orcid.org/0000-0002-4383-342X)
- Lena Annika Street (ORCID: https://orcid.org/0000-0002-5473-6713)
- Sara Olson (ORCID: https://orcid.org/0009-0009-1064-9974)
- Eun‐Jeong Kwon (ORCID: https://orcid.org/0000-0003-4225-0270)
- Maya L. Gosztyla (ORCID: https://orcid.org/0000-0003-4758-4800)
- Grant A. Goda (ORCID: https://orcid.org/0000-0002-7325-2490)
- Wenhao Jin (ORCID: https://orcid.org/0000-0002-7885-3527)
- Easin Uddin Syed (ORCID: https://orcid.org/0000-0002-2225-3231)
- Daniel Dominguez (ORCID: https://orcid.org/0000-0002-8630-2776)
- Eric Kofman (ORCID: https://orcid.org/0000-0001-5462-9099)
- Marko Jovanović (ORCID: https://orcid.org/0000-0001-9707-3377)
- G Yeo
- Allison Li (ORCID: https://orcid.org/0000-0001-5617-0568)
- Xintao Wei
- Jack T. Naritomi (ORCID: https://orcid.org/0000-0001-7746-7467)
- Lijun Zhan (ORCID: https://orcid.org/0000-0003-3982-7884)
- Manya Jain
- Brenton R Graveley
Institutions
- University of North Carolina at Chapel Hill (US)
- Institute for Systems Biology (US)
- University of California San Diego (US)
- Innovative Research (United States) (US)
- Montreal Clinical Research Institute (CA)
- Columbia University (US)
Publication Details
- Journal
- Molecular Cell
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1016/j.molcel.2024.08.010
- Citations
- 32
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 7.48
Funders
- National Science Foundation
- National Sleep Foundation
- Myotonic Dystrophy Foundation
- Association for Women in Science
- Chan Zuckerberg Initiative
- National Institutes of Health
- University of California, San Diego
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Québec - Santé
- National Institute of General Medical Sciences