Transposable element DNA and RNA: Drivers of gene expression, evolution, and disease.

Abstract

Transposable elements (TEs) comprise nearly half of mammalian genomes and have shaped genome architecture, chromatin organization, and transcriptional landscapes. Thanks to recent advances in long-read sequencing and functional (epi)genomics, the focus has shifted from TE families to individual TE loci, revealing widespread, locus-specific regulatory roles. While most TEs have lost the capacity to mobilize, they still retain a DNA form and, when transcribed, an RNA form, both of which can affect genome regulation. TEs can serve as alternative promoters, exons, splicing regulators, and 3' end modulators. They can also act as enhancers, drive three-dimensional (3D) genome organization, and give rise to long non-coding RNAs (lncRNAs) that serve as platforms for transcriptional and chromatin regulators. Mechanistically, TE repression involves DNA methylation, histone modification, phase-separated condensates, RNA modifications, RNA degradation, and nuclear compartmentalization, yet this repression can be selectively lifted during development or stress to expand regulatory potential. TEs therefore contribute to cell-type identity, developmental transitions, and responses to environmental stimuli, while their dysregulation is linked to human disorders including neurodegeneration, cancer, and autoimmune disease. TEs also hold translational promise as biomarkers and tools for gene and cell engineering. In summary, the pervasive integration of TEs as mini-genes, structural scaffolds, and regulatory elements redefines our view of the genome: rather than a gene-centric landscape dotted with repetitive "junk," mammalian DNA is a TE-rich ecosystem in which TEs drive gene regulatory networks and evolution.