Sep. 13, 2023
| 12:00 pm - 1:00 pm ET
Frank Jacobs, Ph.D. – VAI Seminar Series
Disease-associated SVA retrotransposons, G4s and KRAB zinc finger control
Frank Jacobs, Ph.D.
University of Amsterdam
Swammerdam Institute for Life Sciences (SILS)
- Abstract/Bio: Transposable element (TE) invasions have shaped vertebrate genomes over the course of evolution. They have contributed an extra layer of species-specific gene regulation by providing novel transcription factor binding sites. In humans, SVA elements are one of three still active TE families, and approximately 2800 SVA insertions exist in the human genome, half of which are human-specific. Importantly, SVAs harbor a strong gene-regulatory potential and contain several potential G4 quadruplex-forming sequences. Most of these G4s are harbored in the VNTR part of the SVA element, which we recently showed is characterized by an extreme level of structural polymorphism within the human population; fixed SVA insertions, present in all human individuals can exist in many different structural forms, which differ in both G4-content and gene-regulatory potential. Some of those polymorphic SVA insertions reside close to important neurological disease- associated genes and genetic deletion of these SVA elements in iPSC-derived brain tissues results in epigenetic and transcriptomic changes in the respective disease-associated loci. TEs are often silenced by KRAB zinc finger (KZNF) proteins recruiting co-repressor proteins that establish a repressive chromatin state. We previously showed that SVA elements are silenced by the KZNF gene ZNF91, and recent data suggests that ZNF91 binds exactly to the GC rich regions within the SVA that are prone to form G4 Quadruplex structures. Our current work aims to unravel the relationship between the gene-regulatory potential of SVAs, their internal G4s, and ZNF91. This work focusses on the severe neurodegenerative disease ‘X-linked Dystonia Parkinsonism’ (XDP) and the pathogenic influence of the intronic SVA insertion in the TAF1 locus that is the cause for the disorder. For this study, we developed multiple cell- and cortical organoid based models, in an attempt to find ways to neutralize the pathogenic influence which some SVAs can have on genes in their environment.
- Host: Piroska Szabó, Ph.D.