TRANSPOSOstress - Impact of stress-induced transposon activities on human disease

Activitiy code: ERC-2011-AdG-LS
Principal Investigator: Dr. Zsuzsanna Izsvak
Host Institution: Max Delbrück Center for Molecular Medicine (MDC)

Abstract:

The evolutionary success of transposable elements (TEs) is powerfully underscored by the finding that about 45% of the human genome is TE-derived. The vast majority of human TEs are not transpositionally active, and have long been considered to constitute “junk DNA”. However, recent disease-association studies based on high throughput approaches indicate that the impact of TE-associated activities was seriously underestimated. Thus, there is an urgent need to revisit and understand the contribution of TEs to genomic instability and human disease. The objective of this proposal is to investigate the impact of TE-derived activities on the human genome in general and on disease mechanisms in particular, based on the central premise that some of these activities are stress-induced. To model how a vertebrate-specific transposon senses and responds to stress signals in human cells, I will study molecular interactions of the Sleeping Beauty (SB) transposon with host cellular mechanisms to understand how stress-signaling and response triggers transposon activation. This experimental setup mimics a situation of a new TE colonizing a naïve genome. My second aim is to decipher the relationship between stress-induced activation of endogenous TEs and TE-derived regulatory sequences and human disease. In this context, I aim at investigating conditions and the consequences of activation of a particular copy of the MERmaid transposon located in the Sin3B transcriptional corepressor. Transcriptional upregulation of the MERmaid element in this locus may be responsible for deregulated expression of this locus frequently observed in cancer. As TEs are generally regulated epigenetically, the impact of global epigenetic remodeling will be investigated in the model of a complete (induced pluripotency) and partial (trans-differentiation) epigenetic reprogramming. In parallel, I aim at translating experience accumulated in TE research to cutting-edge technologies. First, the SB transposon will be adopted as a safe, therapeutic vector to treat age-dependent blindness (AMD), recently shown to be associated with TE-induced toxicity, in a preclinical and clinical setup. In a different approach, SB vectors modified to contain mutagenic features will be used in a forward genetic screen to decipher a genetic network that protects against hormone-induced mammary cancer in a rat model. The anticipated output of my research programme is a refined understanding of the consequences of environmental stress on our genome mediated by TE-derived sequences. Furthermore, the project is expected to provide an effective bridge between basic research and clinical- as well as technological translation of a novel gene transfer technology. The principal investigator is a pioneer in the field of TE research in vertebrates. Her focus is to understand the basic mechanism of transposition and the interplay between TEs and host cells in mammals. Her team integrates basic knowledge with technologies that are revolutionizing genomic manipulations in vertebrate species, including gene therapy, transgenesis, cancer research and functional genomics.

Project details:

Start date:
End date: negotiation (2012 - 2017)
Total costs: EUR 1 940 725