Research Topics
HERVs are a major component of the human genome. Constituting about 8 - 9% of the genomic DNA, they exceed by far the number of protein-coding gene sequences. Generally, they are extensively controlled and downregulated by genetic and epigenetic mechanisms. Activation by environmental factors such as chemicals, radiation and exogenous retroviruses, however, may lead to expression of undesired HERV gene products and dysregulation of cellular genes by HERV LTR sequences. The aim of our research is to elucidate the biological functions of HERVs, their involvement in evolutionary processes and their possible role in the development of disease. To study these aspects, we have established a method pipeline (Figure 1) in my group generating brain organoids from different brain regions as well as various brain 2D cell models using directed differentiation of human pluripotent stem cells from different origins (patients or different species).
Figure 1: Established method Pipeline. The figure shows the established method pipeline in the laboratory, including gene editing in human embryonic as well as various induced pluripotent stem cells, followed by differentiation in 2D and 3D organoid models of the brain and several techniques to investigate the effects of the introduced changes on brain development and the development of neurodegenerative diseases.
In combination with gene editing technologies (CRISPR; CRISPRi/a), functional underpinning (e.g., calicum imaging, single-cell RNAseq, spatial transcriptomics, Hi-C) and bioinformatics analysis, this pipeline allows us to investigate our current research topics:
1. Human Endogenous Retroviruses in Development
We develop new tools to study the functional role of HERVs during stem cell differentiation into neural cells. We directly manipulate specific HERV groups, using CRISPR technologies, in human stem cells followed by directed differentiation into neural subtypes and generation of brain organoids. In combination with large-scale gene expression analysis we elucidate the functional role and downstream effects of specific HERV groups on neural differentiation.
2. Human Endogenous Retroviruses in Neuropathology
The tight regulation of human endogenous retroviruses (HERVs) is essential for a healthy brain and dysregulation has been associated with neurodegenerative diseases. We are combining the differentiation of stem cells into different human brain cell types with CRISPR activation as well as CRISPR inhibition of specific HERV groups to systematically dissect how dysregulation of HERVs contributes to the development of neuropathology.
3. Regulation of Human Endogenous Retroviruses
Several recent studies suggest that tight regulation of human endogenous retroviruses (HERVs) is essential during developmental processes, e.g. embryonal development, where activation of HERVs leads to regulation of tissue-specific genes. In human brain development, we could show that the exact timing of HERV-K(HML-2) expression is essential for proper cortical brain patterning as well as cortical neurogenesis. We use CRISPR-based approaches in combination with stem cell differetiations, to further understand the precise regulation of HERVs in different brain cell types.
4. Activation of Human Endogenous Retroviruses by Environmental Factors
Activation of human endogenous retroviruses (HERVs) can contribute to disease, including neurodegenrative diseases, through expression of HERV-derived viral proteins or dysregulation of cellular genes. Therefore, we are investigating the effects of various environmental factors (such as exogenous viruses) on HERV activation through transcriptional profiling to understand their impact on reactivation of HERVs and contribution to disease development.