Graduat Student Researcher University of California, San Diego (UCSD), California, United States
Abstract: Retrotransposable elements (RTEs) regulate genomic stability and cellular plasticity, particularly in stem cell populations, but their deregulation is implicated in stem cell aging, inflammation-associated diseases, and malignant transformation. RTEs contribute to genomic instability through retrotransposition, primarily by long interspersed nuclear elements (LINEs), or through epitranscriptomic alterations that activate antiviral inflammatory pathways, particularly via human endogenous retrovirus (HERV) expression. These pathways activate endogenous epitranscriptomic base editors, such as ADAR1 (adenosine deaminase acting on RNA 1) and APOBEC3C (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like type 3C), which evolved to regulate RTE activity in hematopoietic stem and progenitor (HSPC) populations. Notably, both ADAR1 and APOBEC3C overexpression have been linked to HSPC malignant transformation, and their mutational signatures contribute to clonal hematopoiesis and age-associated stem cell decline. Spaceflight represents a unique physiological stressor that may influence RTE expression in a cell-type- and context-specific manner. Here, we quantified retrotransposable element expression in single-cell RNA sequencing data with the scTE pipeline in CD34+-enriched peripheral blood mononuclear cells (PBMCs) from commercial astronauts aboard the Axiom-2 and Axiom-3 missions, sampled before, during, and after spaceflight. Our analysis revealed a transient increase in LINE-1 expression within CD34+ stem cell populations that peaked immediately post-flight and returned to baseline after 21 days. Notably, retroelement activation correlated with longer spaceflight durations, with specific LINE-1 and HERV families differentially expressed in a temporally and cell-type-specific manner alongside base editor activation. These findings provide one of the first insights into RTE activation in HSPCs in response to spaceflight, implicating ADAR1 and APOBEC3C in stress-induced retrotransposable element activity. Understanding how spaceflight influences transposable element regulation may inform strategies to mitigate hematopoietic aging, enhance regenerative medicine applications, and assess long-term health risks associated with space travel.
