Transposable Element Dysregulation in Fetal Down Syndrome Mesenchymal Stem Cells: Insights from a Model of Premature Ageing

Down syndrome (DS) is associated with accelerated biological aging, but the molecular alterations linking trisomy 21 (T21) to early aging-related phenotypes remain incompletely understood. Transposable elements (TEs), particularly LINE-1 (L1) retrotransposons, are sensitive indicators of epigenetic and chromatin instability; however, their dysregulation during fetal development in DS remains largely unexplored. In this study, we performed a bioinformatic analysis of available RNA-sequencing data from chorionic villus-derived fetal mesenchymal stem cells (CV-MSCs) affected by T21 and compared them with data from euploid CV-MSCs. TE expression was quantified using TEtranscripts and analyzed across major TE classes, subfamilies, chromosomes, and evolutionary L1 groups, alongside curated gene-set analyses. At the class level, TE expression showed modest and heterogeneous differences between DS and CTRL samples. Among LINE-1 elements, ancient families, particularly HAL1 and L1M, showed a tendency toward higher expression, whereas L1PA2 and L1HS showed no evidence of increased expression. Pathway analysis revealed downregulation of pathways involved in heterochromatin maintenance and L1 repression, alongside alterations in DNA methylation, the DNA damage response, inflammatory/SASP pathways, nuclear architecture, and mesenchymal commitment. These findings highlight alterations in TE regulation and chromatin-related pathways in fetal DS cells, suggesting that molecular features potentially relevant to accelerated aging may be detectable early during development.