Regulatory Roles of Noncoding RNAs in Gene Expression and Cellular Stress Responses

/Abstract Over the past decade, our understanding of regulatory noncoding RNAs (ncRNAs) has expanded significantly, revealing their critical roles in controlling gene expression during development, stress responses, and disease. This project focuses on elucidating the mechanisms driving the biogenesis, regulation, and function of an emerging class of ncRNAs known as downstream-of-gene (DoG) RNAs. Our lab recently identified these unannotated transcripts, which extend beyond the ends of their host genes, exhibit tissue-specific expression patterns, and are induced under transcriptional stress caused by defects in RNA Polymerase II (RNAPII) pausing and Topoisomerase 1 (TOP1) inhibition. Preliminary findings suggest that DoG RNAs may function as long enhancer RNAs (eRNAs), regulating chromatin structure and gene expression through mechanisms that remain unexplored. Building on our prior work characterizing eRNAs and their direct roles in chromatin and gene regulation, this project will investigate the molecular pathways driving DoG RNA biogenesis and processing, as well as their functional roles in transcriptional stress responses and cellular homeostasis. Leveraging advanced genomic, biochemical, and computational approaches, including PRO-seq, RNA-seq, and ChIP-seq, we aim to uncover novel ncRNA-dependent regulatory pathways and elucidate how DoG RNAs modulate chromatin accessibility, transcriptional dynamics, and 3D genome organization. By addressing these fundamental questions, this research will provide critical insights into the biology of stress-induced ncRNAs and their roles in transcriptional fidelity. The findings will not only deepen our understanding of ncRNA-mediated gene regulation but also identify potential therapeutic targets for restoring transcriptional homeostasis in diseases such as cancer, where transcriptional dysregulation plays a central role. This work represents a transformative step in ncRNA research, paving the way for the development of ncRNA- and RNA binding protein-based therapeutics. Project Number: 1R35GM161368-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Shannon Lauberth | Institution: NORTHWESTERN UNIVERSITY, CHICAGO, IL | Award Amount: $440,000 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - F Study Section[MRAF] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260356