Yaara Finkel

All Publications

• High-throughput discovery of regulatory effector domains in human RNA-binding proteins. bioRxiv : the preprint server for biology Thurm, A. R., Finkel, Y., Andrews, C., Cai, X. S., Benko, C., Bintu, L. 2024

  Abstract

  RNA regulation plays an integral role in tuning gene expression and is controlled by thousands of RNA-binding proteins (RBPs). We develop and use a high-throughput recruitment assay (HT-RNA-Recruit) to identify regulatory domains within human RBPs by recruiting over 30,000 protein tiles from 367 RBPs to a reporter mRNA. We discover over 100 unique RNA-regulatory effectors in 86 distinct RBPs, presenting evidence that RBPs contain functionally separable domains that dictate their post-transcriptional control of gene expression, and identify some with unique activity at 5' or 3'UTRs. We identify some domains that downregulate gene expression both when recruited to DNA and RNA, and dissect their mechanisms of regulation. Finally, we build a synthetic RNA regulator that can stably maintain gene expression at desired levels that are predictable by a mathematical model. This work serves as a resource for human RNA-regulatory effectors and expands the synthetic repertoire of RNA-based genetic control tools.Highlights: HT-RNA-Recruit identifies hundreds of RNA-regulatory effectors in human proteins.Recruitment to 5' and 3' UTRs identifies regulatory domains unique to each position.Some protein domains have both transcriptional and post-transcriptional regulatory activity.We develop a synthetic RNA regulator and a mathematical model to describe its behavior.

  View details for DOI 10.1101/2024.07.19.604317

  View details for PubMedID 39071298

• A virally encoded high-resolution screen of cytomegalovirus dependencies. Nature Finkel, Y., Nachshon, A., Aharon, E., Arazi, T., Simonovsky, E., Dobesova, M., Saud, Z., Gluck, A., Fisher, T., Stanton, R. J., Schwartz, M., Stern-Ginossar, N. 2024; 630 (8017): 712-719

  Abstract

  Genetic screens have transformed our ability to interrogate cellular factor requirements for viral infections1,2, but most current approaches are limited in their sensitivity, biased towards early stages of infection and provide only simplistic phenotypic information that is often based on survival of infected cells2-4. Here, by engineering human cytomegalovirus to express single guide RNA libraries directly from the viral genome, we developed virus-encoded CRISPR-based direct readout screening (VECOS), a sensitive, versatile, viral-centric approach that enables profiling of different stages of viral infection in a pooled format. Using this approach, we identified hundreds of host dependency and restriction factors and quantified their direct effects on viral genome replication, viral particle secretion and infectiousness of secreted particles, providing a multi-dimensional perspective on virus-host interactions. These high-resolution measurements reveal that perturbations altering late stages in the life cycle of human cytomegalovirus (HCMV) mostly regulate viral particle quality rather than quantity, establishing correct virion assembly as a critical stage that is heavily reliant on virus-host interactions. Overall, VECOS facilitates systematic high-resolution dissection of the role of human proteins during the infection cycle, providing a roadmap for in-depth study of host-herpesvirus interactions.

  View details for DOI 10.1038/s41586-024-07503-z

  View details for PubMedID 38839957