Quadruplex structures in mobile DNA Next-level regulation of transposable elements in the human genome

Quadruplex structures, non-canonical DNA configurations, are central to the evolution and regulation of mobile genetic elements, such as transposable elements (TEs). These elements drive genetic diversity and adaptability, playing a significant role in neurogenomics by influencing neural complexity and plasticity. The objective of this thesis was to increase our understanding of the influence of TEs and their G4 structures on human gene expression, particularly in brain evolution, development, and health.
Epigenetic mechanisms, particularly DNA methylation, are critical in modulating TE activity. KRAB-ZNF proteins work alongside these mechanisms to control TE activity, safeguarding genomic stability. This regulation is crucial in shaping 3D-DNA architecture, as the interplay of active and repressed chromatin regions influences spatial genome organization during critical stages of development. Genome-wide methylation assays in human embryonic stem cells and cortical organoids revealed that certain young TE subclasses lose repression through hypomethylation, becoming reactivated during early brain development.
In addition, primate-specific TEs, particularly the G4-dense SVA elements, exhibit significant potential for forming G4 structures. Genome-wide tools and in vivo G4-specific antibody mapping have indicated that younger TE subtypes have a higher G4 potential, though G4 formation is tightly controlled and cell type-specific. Additionally, the interaction between SVA and ZNF91 highlights molecular mechanisms underlying intronic SVA insertions, contributing to disorders such as X-linked dystonia parkinsonism (XDP), where an SVA insertion in TAF1 disrupts transcription.
This work advances understanding of human cortical development and demonstrates that many young TEs contribute secondary DNA structures to gene regulatory networks.