Integrated Multi-omics Analysis of Zinc-finger Proteins Uncovers Roles in RNA Regulation

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2024 Sep 20

PMID 39303722

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 Lecuyer

Daniel Dominguez

Marko Jovanovic

Brenton R Graveley

Gene W Yeo

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Alternative Splicing in the Heart: The Therapeutic Potential of Regulating the Regulators.

Briganti F, Wang Z Int J Mol Sci. 2024; 25(23.

PMID: 39684734 PMC: 11641712. DOI: 10.3390/ijms252313023.

References

Van Nostrand E, Pratt G, Shishkin A, Gelboin-Burkhart C, Fang M, Sundararaman B . Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat Methods. 2016; 13(6):508-14. PMC: 4887338. DOI: 10.1038/nmeth.3810. View

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O . Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1):1523. PMC: 6447622. DOI: 10.1038/s41467-019-09234-6. View

Nogueira G, Fernandes R, Garcia-Moreno J, Romao L . Nonsense-mediated RNA decay and its bipolar function in cancer. Mol Cancer. 2021; 20(1):72. PMC: 8082775. DOI: 10.1186/s12943-021-01364-0. View

Gebauer F, Schwarzl T, Valcarcel J, Hentze M . RNA-binding proteins in human genetic disease. Nat Rev Genet. 2020; 22(3):185-198. DOI: 10.1038/s41576-020-00302-y. View

Burdach J, OConnell M, Mackay J, Crossley M . Two-timing zinc finger transcription factors liaising with RNA. Trends Biochem Sci. 2012; 37(5):199-205. DOI: 10.1016/j.tibs.2012.02.001. View

Van Nostrand E, Freese P, Pratt G, Wang X, Wei X, Xiao R . A large-scale binding and functional map of human RNA-binding proteins. Nature. 2020; 583(7818):711-719. PMC: 7410833. DOI: 10.1038/s41586-020-2077-3. View

Erdos G, Pajkos M, Dosztanyi Z . IUPred3: prediction of protein disorder enhanced with unambiguous experimental annotation and visualization of evolutionary conservation. Nucleic Acids Res. 2021; 49(W1):W297-W303. PMC: 8262696. DOI: 10.1093/nar/gkab408. View

Cassandri M, Smirnov A, Novelli F, Pitolli C, Agostini M, Malewicz M . Zinc-finger proteins in health and disease. Cell Death Discov. 2017; 3:17071. PMC: 5683310. DOI: 10.1038/cddiscovery.2017.71. View

Goering R, Engel K, Gillen A, Fong N, Bentley D, Taliaferro J . LABRAT reveals association of alternative polyadenylation with transcript localization, RNA binding protein expression, transcription speed, and cancer survival. BMC Genomics. 2021; 22(1):476. PMC: 8234626. DOI: 10.1186/s12864-021-07781-1. View

10.

Singh G, Kucukural A, Cenik C, Leszyk J, Shaffer S, Weng Z . The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell. 2012; 151(4):750-764. PMC: 3522173. DOI: 10.1016/j.cell.2012.10.007. View

11.

Xiao R, Chen J, Liang Z, Luo D, Chen G, Lu Z . Pervasive Chromatin-RNA Binding Protein Interactions Enable RNA-Based Regulation of Transcription. Cell. 2019; 178(1):107-121.e18. PMC: 6760001. DOI: 10.1016/j.cell.2019.06.001. View

12.

Mitchell S, Parker R . Principles and properties of eukaryotic mRNPs. Mol Cell. 2014; 54(4):547-58. DOI: 10.1016/j.molcel.2014.04.033. View

13.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

14.

Trendel J, Schwarzl T, Horos R, Prakash A, Bateman A, Hentze M . The Human RNA-Binding Proteome and Its Dynamics during Translational Arrest. Cell. 2018; 176(1-2):391-403.e19. DOI: 10.1016/j.cell.2018.11.004. View

15.

Glover-Cutter K, Kim S, Espinosa J, Bentley D . RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat Struct Mol Biol. 2007; 15(1):71-8. PMC: 2836588. DOI: 10.1038/nsmb1352. View

16.

Skene P, Henikoff S . An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. Elife. 2017; 6. PMC: 5310842. DOI: 10.7554/eLife.21856. View

17.

Petasny M, Bentata M, Pawellek A, Baker M, Kay G, Salton M . Splicing to Keep Cycling: The Importance of Pre-mRNA Splicing during the Cell Cycle. Trends Genet. 2020; 37(3):266-278. DOI: 10.1016/j.tig.2020.08.013. View

18.

Luo E, Nathanson J, Tan F, Schwartz J, Schmok J, Shankar A . Large-scale tethered function assays identify factors that regulate mRNA stability and translation. Nat Struct Mol Biol. 2020; 27(10):989-1000. PMC: 8221285. DOI: 10.1038/s41594-020-0477-6. View

19.

Zhang Z, Liu T, Dong H, Li J, Sun H, Qian X . An RNA tagging approach for system-wide RNA-binding proteome profiling and dynamics investigation upon transcription inhibition. Nucleic Acids Res. 2021; 49(11):e65. PMC: 8216453. DOI: 10.1093/nar/gkab156. View

20.

Li W, Deng X, Chen J . RNA-binding proteins in regulating mRNA stability and translation: roles and mechanisms in cancer. Semin Cancer Biol. 2022; 86(Pt 2):664-677. PMC: 9526761. DOI: 10.1016/j.semcancer.2022.03.025. View