Shaping the transcriptome through autophagy

In the face of environmental stress, autophagy plays a crucial role in stress adaptation through the maintenance of cellular homeostasis. While extensively studied for its ability to degrade proteins, pathogens, and organelles, the potential of autophagy to degrade RNA remains largely unexplored. Recent findings from my team uniquely reveal that specific subsets of RNA are selectively sequestered and degraded by autophagy in a stress-responsive manner. However, the molecular mechanisms driving this process and its biological implications remain unknown. Based on our preliminary results, I hypothesize that autophagy represents a previously unrecognized, highly regulated RNA decay pathway capable of dynamically shaping the transcriptome in response to cellular stress.Here, I propose a comprehensive approach to investigate autophagy's impact on transcriptome remodeling in response to hypoxia and UV irradiation in cellular models and during melanoma development in mice. To this end, I will integrate state-of-the-art sequencing technologies with subcellular proteomics, high-content screening, advanced biochemistry, and single molecule RNA imaging. In doing so, we will dissect the molecular signals and regulatory factors guiding this previously overlooked RNA decay pathway. Furthermore, we will determine the biological consequences of pathway dysfunction on transcriptome integrity, cellular fitness, and the shaping of cellular identity. Together, this work will provide crucial insights into the mechanisms governing RNA homeostasis during cellular stress. The findings will challenge our current view of autophagy and uncover fundamental new understanding of gene expression regulation in health and disease, with broad implications across the biological sciences.