Regulation of transposable elements during early mammalian development

Hermant, Clara (2025): Regulation of transposable elements during early mammalian development. Dissertation, LMU München: Fakultät für Biologie

Abstract

Transposable elements (TEs) are mobile genetic elements that make up a significant portion of mammalian genomes. They have evolved cis-regulatory elements to hijack host-encoded transcription machinery for their own expression. While typically silenced in somatic cells, TEs undergo a dramatic and stage-specific surge in transcriptional activity during early mammalian development, particularly around the time of genome activation. Once considered a byproduct of epigenetic reprogramming, TE expression is now emerging as a tightly regulated process with critical biological implications. Understanding the molecular mechanisms mediating TE expression, particularly during critical stages such as preimplantation development, is of utmost importance. We hypothesized that, like genes, TEs are regulated by sequence-specific transcription factors (TFs) and are under evolutionary pressure to preserve TF binding sites (TFBS) for factors expressed during these developmental stages. In this study, we aimed to identify novel TFs involved in regulating six highly expressed TE families in the mouse embryo. By analyzing chromatin accessibility data, we identified 54 candidate TFs potentially involved in TE regulation. Phylogenetic analysis, combined with TFBS profiling over individual insertions, revealed correlations between TE subfamilies, TFBS and expression patterns during development. We reconstructed the evolutionary history of MERVL LTRs, identifying SRF as a regulator of MT2, and pinpointed the acquisition of SRF and DUX binding sites during MT2 evolution. A targeted gain-of-function screen in mESCs showed that 10 TFs induced TE transcription, and luciferase reporter assays confirmed the role of SRF as an activator of MT2. Three TFs, SRF, FOXJ3 and TBP, were further investigated for their functional roles in TE regulation in-vivo. Loss of function (LOF) experiments confirmed the role of SRF as a regulator of MERVL at the 2-cell stage, while TBP was found to regulate MaLR ORR. Together, this work sheds light on TE regulation during early mammalian development, and identifed SRF and TBP as novel regulators of TEs, expanding our understanding of the dynamic interplay between TFs and TEs in early embryogenesis.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Preimplantation Development, Transposable Elements, Transcription Factors, Regulatory Evolution
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 4. Dezember 2025
• 1. Bericht­erstatter:in: Torres-Padilla, Maria Elena