ERC FUNDED PROJECTS

The rapidly changing climate puts commonly used crop plants under strong pressure. It is therefore essential to develop novel breeding technologies to rapidly enhance crops to better withstand newly emerging stresses. Interestingly, a clear link between transposable elements (TEs), crop improvement and varietal diversification exists. Furthermore, in recent years the importance of (TEs) in evolution and adaptation to stresses has been recognized. However the use of TEs in crop breeding is currently very limited because it is not possible to control TE mobility. My research group has identified a novel highly conserved epigenetic silencing mechanism that represses the activity of TEs in Arabidopsis. We also found drugs capable of inhibiting this mechanism. Because these drugs target highly conserved enzymes we were able to show that our drug treatment is also effective in rice. We are therefore able to produce TE bursts in a controlled manner in virtually any plant. We can thus, for the first time, generate and study TE bursts in crop plants in real time. More importantly, we found that the accumulation of novel insertions of a heat-stress inducible TE produced plants that, at a high frequency, were more resistant to heat stress. This suggests that the stress that was initially applied to activate a specific TE in the parent, lead to an improved tolerance to that specific stress in the progeny of that plant in a very straight-forward manner. In this project I propose to accelerate plant breeding by testing and implementing a revolutionary TE-directed crop improvement technology. For that I plan to 1. Mobilize TEs in crop plants using selected stresses 2. Using these mobilized stress-responsive TEs breed novel crop plants resistant to those selected stresses and 3. Study the genetic and epigenetic impact of TE mobilization on host genomes. This project will have a broad impact on crop improvement and on the basic understanding of the evolutionary importance of TEs.

1 965 625 €

Start date: 2017-06-01, End date: 2022-05-31

Cholera is one of the oldest infectious diseases known and remains a major burden in many developing countries. The World Health Organization estimates that up to 4 million cases of cholera occur annually. The transmission of cholera by contaminated water, particularly under epidemic conditions, was first reported in the 19th century. However, early volunteer studies suggested that an incredibly high infectious dose (ID) is required to produce disease symptoms, in contrast to most other intestinal pathogens. Therefore, the mechanism of infection of index cases at the onset of an outbreak is unclear. This proposal aims to fill this knowledge gap by studying how the environmental lifestyle of the causative agent of the disease, the bacterium Vibrio cholerae, may prime the pathogen for intestinal colonization. We hypothesize that one of the natural niches of the bacterium (chitinous surfaces) fosters biofilm formation and provides a competitive advantage over co-colonizing bacteria. As an adaptive trait, passage of chitin-attached sessile V. cholerae through the acidic environment of the human stomach might be vastly facilitated compared to planktonic bacteria. Moreover, interbacterial warfare exerted by V. cholerae on these biotic surfaces may help the pathogen overcome the colonization barrier imposed by the human microbiota upon ingestion. The mechanism by which V. cholerae leaves the sessile lifestyle and the regulatory circuits involved in this process will also be investigated in this project. In summary, our goal is to elucidate the environmental community structures of V. cholerae that may enhance transmissibility from the ecosystem to humans in endemic areas resulting in the infection of index cases.

1 999 988 €

Start date: 2018-02-01, End date: 2023-01-31

Organismal development requires proper timing of events such as cell fate choices, but the mechanisms that control temporal patterning remain poorly understood. In particular, we know little of the cyclical timers, or ‘clocks’, that control recurring events such as vertebrate segmentation or nematode molting. Furthermore, it is unknown how cyclical timers are coordinated with the global, or linear, timing of development, e.g. to ensure an appropriate number of cyclical repeats. We propose to elucidate the components, wiring, and properties of a prototypic developmental clock by studying developmental timing in the roundworm C. elegans. We build on our recent discovery that nearly 20% of the worm’s transcriptome oscillates during larval development – an apparent manifestation of a clock that times the various recurring events that encompass each larval stage. Our aims are i) to identify components of this clock using genetic screens, ii) to gain insight into the system’s architecture and properties by employing specific perturbations such as food deprivation, and iii) to understand the coupling of this cyclic clock to the linear heterochronic timer through genetic manipulations. To achieve our ambitious goals, we will develop tools for mRNA sequencing of individual worms and for their developmental tracking and microchamber-based imaging. These important advances will increase temporal resolution, enhance signal-to-noise ratio, and achieve live tracking of oscillations in vivo. Our combination of genetic, genomic, imaging, and computational approaches will provide a detailed understanding of this clock, and biological timing mechanisms in general. As heterochronic genes and rhythmic gene expression are also important for controlling stem cell fates, we foresee that the results gained will additionally reveal regulatory mechanisms of stem cells, thus advancing our fundamental understanding of animal development and future applications in regenerative medicine.

2 358 625 €

Start date: 2017-10-01, End date: 2022-09-30

Epigenetic inheritance is the transmission of information, generally in the form of DNA methylation or post-translational modifications on histones that regulate the availability of underlying genetic information for transcription. RNA itself feeds back to contribute to histone modification. Sequence accessibility is both a matter of folding the chromatin fibre to alter access to recognition motifs, and the local concentration of factors needed for efficient transcriptional initiation, elongation, termination or mRNA stability. In heterochromatin we find a subset of regulatory factors in carefully balanced concentrations that are maintained in part by the segregation of active and inactive domains. Histone H3 K9 methylation is key to this compartmentation. C. elegans provides an ideal system in which to study chromatin-based gene repression. We have demonstrated that histone H3 K9 methylation is the essential signal for the sequestration of heterochromatin at the nuclear envelope in C. elegans. The recognition of H3K9me1/2/3 by an inner nuclear envelope-bound chromodomain protein, CEC-4, actively sequesters heterochromatin in embryos, and contributes redundantly in adult tissues. Epiherigans has the ambitious goal to determine definitively what targets H3K9 methylation, and identify its physiological roles. We will examine how this mark contributes to the epigenetic recognition of repeat vs non-repeat sequence, and mediates a stress-induced response to oxidative damage. We will examine the link between these and the spatial clustering of heterochromatic domains. Epiherigans will develop an integrated approach to identify in vivo the factors that distinguish repeats from non-repeats, self from non-self within genomes and will examine how H3K9me contributes to a persistent ROS or DNA damage stress response. It represents a crucial step towards understanding of how our genomes use heterochromatin to modulate, stabilize and transmit chromatin organization.

2 500 000 €

Start date: 2017-06-01, End date: 2022-05-31