In Vitro Characterization of the CHROMR lncRNA IRF2BP2 Protein Interaction

ABSTRACT

Understanding gene regulation is crucial for elucidating biological processes and their impact on health and disease. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators in these processes, yet the specific roles of their structural dynamics in biological pathways remain incompletely understood. The cholesterol-induced regulator of metabolism RNA (CHROMR) is a primate-specific lncRNA that regulates cholesterol metabolism and is hypothesized to mediate the response to viral infections through the sequestration of the interferon regulatory factor binding protein 2 (IRF2BP2). IRF2BP2 regulates the innate immune response by forming the IRF2-IRF2BP2 transcriptional corepressor complex. Until now, the interaction between CHROMR and IRF2BP2 is uncharacterized. Using bioinformatics and biochemical assays, we determined the secondary structure of CHROMR, revealing that folds form three structured domains, and have characterized the interaction interface between CHROMR and IRF2BP2. Our results reveal that the N-terminal zinc finger of IRF2BP2 is primarily responsible for driving its interaction with CHROMR, and, that there are multiple binding sites for IRF2BP2 along the length of CHROMR. This study reveals the structural mechanism that enables CHROMR to function as a critical regulator in the innate immune response against viral infections.

BIOGRAPHY

Dr. Alisha ‘Jonesy’ Jones, one of C&EN News 2024 Talented Twelve, is a James Weldon Johnson Assistant Professor of Chemistry at New York University in the Department of Chemistry. Jonesy was a postdoctoral researcher in the lab of Dr. Michael Sattler in Munich, Germany, and earned her PhD in Chemistry in the lab of Dr. Gabriele Varani at the University of Washington. Research in the Jones Lab focuses on investigating the structural dynamics of long noncoding RNAs (lncRNAs) and how they are linked to specific biological processes. Her team deploys a combination of biophysical, biochemical, and computational techniques to study how lncRNAs transition between various structured states and how they interact with other biomolecules. Considering that lncRNAs are critical regulators of gene expression, her lab’s work has the potential to increase overall knowledge regarding lncRNA structure-function relationships and offers a starting point for therapeutically targeting lncRNAs when they are implicated in a disease.