Research topics

1. Investigating the functional role of HERVs on stem cell differentiation and brain development

One of the most surprising findings of the human genome project was that about 50% of our genome consists of viral elements, so called DNA-transposons and retrotransposons including human endogenous retroviral (HERV) elements, which total up to 9% of the human genome. Initially, HERVs have been considered as "Junk-DNA" or genomic parasites, but studies of recent years have provided compelling evidence that HERVs critically influence genome functions mainly through transcriptional control. They are now suggested as an important force in the genome evolution and adaptation of an organism to altered environmental conditions. So far strong focus has been devoted to the relationship of HERVs and the onset or progression of diseases. Here, HERV expression has been studied in samples of pathological origin. Although important, these studies do not provide conclusions about whether HERVs are the cause or the effect of such disease. As each group of HERVs can consist of several hundred to thousands of sequences, it is a challenging task to perform functional analyses and identify the impact of specific HERV groups on certain biological processes. 

My laboratory developes new tools to study the functional role of HERVs in stem cell differentiation to neural cells. We directly manipulate specific HERV groups, using CRISPRactivation (CRISPRa) as well as CRISPRinhibition (CRISPRi) in hPSCs followed by directed differentiation into neural subtypes and generation of brain organoids (Fig. 1). We further perform large-scale gene expression analysis to elucidate the functional role and downstream effects of specific HERV groups on neural differentiation. 

Fig. 1 Cortical neurons and brain organoids differentiated from pluripotent stem cells

 

 

2. Influence of exogenous pathogens on the expression of endogenous retroviruses
Activation of human endogenous retroviral sequences can contribute to diseases by 
expression of pathogenic viral proteins or dysregulation of cellular genes. We are 
currently investigating the interaction of various exogenous viruses and other infectious agents with HERVs by transcription profiling and identification of differentially active genomic HERV loci (Fig. 2).

Fig. 2 HERV transcription profiles of HIV-1 infected cell lines using a retrovirus-specific microarray (Vincendeau et al., Retrovirology, 2015, PMID 25886562)

 

3. Retrovirus-specific microarray
The Retrovirus-specific DNA chip is based on the reverse transcriptase domain of retroviral pol genes and comprises representatives of all major HERV groups, as well as exogenous human retroviruses and animal retroviruses. The microarray can be used, for example, to determine endogenous and exogenous retroviral activity in human tissues and cells, to assess purity and homogeneity of human and mammalian cell lines, to survey xenotransplants and transplant recipients and to monitor packaging cell lines and vector preparations to exclude cotransfer of recombination competent retroviruses (RCR) and endogenous retroviruses (Seifarth et al., 2003, Vincendeau et al., 2015).

RetroArray brochure

Tissue-specific HERV expression profiles could be established for all human tissues investigated so far using the retrovirus-specific microarray (Fig 3). No tissue completely lacking HERV transcription was found, confirming that HERVs are permanent components of the human transcriptome (Seifarth et al., 2005). Most active HERVs were identified in skin, thyroid gland, placenta and in tissues of reproductive organs.

Fig. 3(a,b) HERV expression profiles in human tissues