Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT: Cells of the Caenorhabditis elegans early embryo diversify their mRNA content even in the absence of de novo transcription. This remarkable feat has given my lab a unique vantage from which to study post- transcriptional regulation. Surprisingly, we found that many mRNA transcripts which exhibit cell-specific patterning also localize to discrete subcellular structures such as biomolecular condensates or membranes. My lab aims to understand how subcellular mRNA patterning arises mechanistically, how it functionally links to protein production, and how it impacts development. Recent advances have identified 190,000 localized mRNA transcripts found at 44 subcellular locales across 65 species (RNALocate Database). These transcripts include many that impact human neurobiology and whose mislocalization is associated with disease. Many more represent mRNAs that accumulate at cellular regions through unknown mechanisms and for undefined purposes, underscoring the potential for new discoveries that we aim to make. In the first funding phase, my group determined mechanisms that localize mRNAs to P granules (cytoplasmic condensates important for germline development and fertility). Transcripts that associate with P granules undergo either temporary sequestration or permanent decay. In the next phase, we will address the signals, mechanisms, and dynamics that distinguish P granule-associated mRNA sequestration from decay. Specifically, we will differentiate between competing models explaining how the conserved transcript nos-2 (nanos) exits P granules and initiates its translation to ensure fertility. Previously, we identified several mRNA transcripts that localize to membranes along with the proteins they encode, a finding echoed in other organisms. Among these were erm-1 a member of a conserved family of cytoskeletal membrane linker proteins that impacts cell shape and cancer. We found that erm-1’s mRNA localization is translation-dependent. Next, we will address the mechanisms and principles explaining how and why complexes of translating erm-1 move to membranes. We will also use genomics to characterize the membrane-enriched transcriptome to better understand localized translation at membranes. Maternal mRNA transcripts undergo decay in early embryos often creating cell-specific patterns that direct cell differentiation. In the first funding cycle, we demonstrated a requirement for the RNA binding protein SPN-4 in the clearance and cell-specificity of some transcripts. In the next phase, we will determine how SPN-4 shapes the transcriptome and works in concert with other mechanisms of mRNA clearance. The sum of these projects will be to create an overarching research program aimed at describing how mRNA transcripts organize spatially within the cell and how that organization can impact gene expression and embryogenesis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
