RNA dynamics and co-translational decay in aging and aging-related disease

National Institute On Aging

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Abstract

While genomes encapsulate the information for the development and function of cells most of the biological complexity lies on high-order interactions and gene regulatory programs. Dissecting these regulatory mechanisms is critical for understanding complex, polygenic processes such as aging. In previous works we described a co-translational pathway of mRNA decay that is mediated by ribosome-phased cleavage of the mRNA (Ibrahim et al., 2018). There we developed a new experimental protocol to capture the native ends of mRNAs. However, the available protocols are limited as they cannot capture both the 5' and 3' ends simultaneously on the same molecule. This limited our ability to probe mRNA properties. We therefore developed, experimental/computational approaches to capture the native ends of mRNA molecules using direct RNA, nanopore sequencing. We have applied these protocols to analyze RNA metabolism (transcription and decay rates) in cellular stress and in aging animal tissues as well as isoform dynamics across cell-types. We also employ machine learning to extract information about post-transcriptional RNA modifications from raw nanopore electrical signal which we use to more accurately probe RNA metabolism.