Title: Studying RNA Binding Proteins at Subcellular Resolution to Uncover their Roles in Health and Dysregulation in Disease
Abstract: Regulation of gene expression is at the basis of cell function. It is well established how the multitude of cellular signals is transduced to regulate transcription. In contrast, it remains to be defined how signals and cellular pathways are wired to factors that regulate gene expression post-transcriptionally (such as RNA BindingProteins and noncoding RNAs). This conceptual gap stems from technical challenges but is reflected in the relatively detached fields of RNA biology and cell biology.
I will present concepts learned while studying the function of CNBP, an RNA Binding Protein that is conserved throughout eukaryotes, and causative for Myotonic dystrophy type 2. While identifying CNBP function we uncovered the dominant effect of RNAG-quadruplex structures when they are formed in the cytoplasm (Benhalevy*,Gupta* et al. Cell Reports, 2017, Sauer, …, Benhalevyet al. Nature Comm, 2019). Our more recent analyses hint at a possible mechanism for why CNBP mutations elicit specifically a muscle disease, but testing our model requires studying RNA biology at subcellular resolution. I will show why studying RNA Binding Proteins at subcellular resolution is often crucial, and why it is a challenge. Then I will present novel methodologies I developed to study RNA biology at subcellular resolution that overcomes this challenge (Benhalevy* et al. Methods, 2017, Benhalevyet al. Nature Methods, 2018, Benhalevy† and Hafner†,MiMB, 2020, Anastasakis*, Benhalevy*† etal. CPMB, 2020, and unpublished data).
These results enable me to pursue the following research goals: 1. Applying concrete, in-depth, study of RNA regulation at subcellular resolution to infer general concepts in post-transcriptional gene regulation. In the long run, these will contribute to linking RNA biology with pathways of cellular biology. 2. Developing unprecedented tools to study subcellular RNA biology in uncultured cells with direct applicability to human tissue-derived cells, and with the intention to expose new aspects of RNA biology in health and disease
Host: Sagi Levy