ERC FUNDED PROJECTS

Over 100 types of distinct modifications are catalyzed on RNA molecules post-transcriptionally. In an analogous manner to well-studied chemical modifications on proteins or DNA, modifications on RNA - and particularly on mRNA - harbor the exciting potential of regulating the complex and interlinked life cycle of these molecules. The most abundant modification in mammalian and yeast mRNA is N6-methyladenosine (m6A). We have pioneered approaches for mapping m6A in a transcriptome wide manner, and we and others have identified factors involved in encoding and decoding m6A. While experimental disruption of these factors is associated with severe phenotypes, the role of m6A remains enigmatic. No single methylated site has been shown to causally underlie any physiological or molecular function. This proposal aims to establish a framework for systematically deciphering the molecular function of a modification and its underlying mechanisms and to uncover the physiological role of the modification in regulation of a cellular response. We will apply this framework to m6A in the context of meiosis in budding yeast, as m6A dynamically accumulates on meiotic mRNAs and as the methyltransferase catalyzing m6A is essential for meiosis. We will (1) aim to elucidate the physiological targets of methylation governing entry into meiosis (2) seek to elucidate the function of m6A at the molecular level, and understand its impact on the various steps of the mRNA life cycle, (3) seek to understand the mechanisms underlying its effects. These aims will provide a comprehensive framework for understanding how the epitranscriptome, an emerging post-transcriptional layer of regulation, fine-tunes gene regulation and impacts cellular decision making in a dynamic response, and will set the stage towards dissecting the roles of m6A and of an expanding set of mRNA modifications in more complex and disease related systems.

1 402 666 €

Start date: 2016-11-01, End date: 2021-10-31

Trade unions play a major role in democratic interest intermediation. This role is currently threatened by the increasingly authoritarian strain in EU’s new economic governance (NEG). This project aims to explore the challenges and possibilities that the NEG poses to labour politics. Until recently, European labour politics has mainly been shaped by horizontal market integration through the free movement of goods, capital, services and people. After the financial crisis, the latter has been complemented by vertical integration effected through the direct surveillance of member states. The resulting NEG opens contradictory possibilities for labour movements in Europe. On the one hand, the reliance of the NEG on vertical surveillance makes decisions taken in its name more tangible, offering concrete targets for contentious transnational collective action. On the other hand however, the NEG mimics the governance structures of multinational firms, by using key performance indicators that put countries in competition with one another. This constitutes a deterrent to transnational collective action. The NEG’s interventionist and competitive strains also pose the threat of nationalist counter-movements, thus making European collective action ever more vital for the future of EU integration and democracy. This project has the following objectives: 1. To understand the interrelation between NEG and existing ‘horizontal’ EU economic governance; and the shifts in labour politics triggered by NEG; 2. To open up novel analytical approaches that are able to capture both national and transnational social processes at work; 3. To analyse the responses of established trade unions and new social movements to NEG in selected subject areas and economic sectors at national and EU levels, and their feedback effects on NEG; 4. To develop a new scientific paradigm capable of accounting for the interplay between EU economic governance, labour politics and EU democracy.

1 997 132 €

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

Reversible epigenetic modifications regulate gene expression to define cell fate and response to environmental stimuli. Gene expression tuning by DNA and chromatin modifications is well studied, yet the effect of RNA modifications on gene expression is only starting to be revealed. More than a hundred chemical modifications decorate RNAs, mainly non-coding ones, expanding their nucleotide vocabulary and mediating their diverse functions. Several modifications were globally mapped in mRNA. Only two, N6-methyladenosine (m6A) and N1-methyladenosine (m1A) exhibit a distinct topology alluding to a functional role. We pioneered the identification of m6A that is located preferentially in distinct transcript landmarks, mostly around stop codons and mediates transcript localization, splicing, decay and translation. We now identified m1A which decorates thousands of genes mainly in the start codon vicinity, upstream to the first splice site. Our preliminary results indicate that m1A dynamically responds to environmental stimuli and plays a central role in translation regulation. The regulation and functions of m1A are still terra incognita. Our objectives are to identify m1A writers and erasers, elucidate m1A readers and the mechanisms whereby m1A dictates downstream outcomes, particularly translation regulation. We will study m1A functions in response to physiologic stimuli and stress conditions in cells and animal models by manipulation of the m1A deposition machinery. As epigenetic marks operate in a context-dependent concerted way we will map m1A marks concomitantly with m6A to decipher their interplay in regulating gene expression via a putative “epigenetic RNA code”. The data obtained from parallel mapping of m1A and m6A at a single nucleotide and a single transcript resolution, will expose the interplay between these two mRNA modifications in the context of multilayer epigenetics. The study of m1A circuits may identify targets amenable to therapeutic manipulations.

2 457 500 €

Start date: 2017-07-01, End date: 2022-06-30

Robust and flexible tissue- and cell-type specific gene regulation is a definitive prerequisite for complex function in any multi-cellular organism. Modern genomics and epigenomics provide us with catalogues of gene regulatory elements and maps illustrating their activity in different tissues. Nevertheless, we are far from being able to explain emergence and maintenance of cellular states from such data, partly because we so far lacked characterization of individual molecular states and genome control mechanisms at their native resolution - the single cell. Recently, new approaches developed by the single cell genomics community, with several contributions from our group, allow massive acquisition of data on the transcriptional, epigenomic and chromosomal conformation states in large cohorts of single cells. In this research program, we aim to move forward rapidly to bridge a major gap between these experimental breakthroughs and models of genome regulation in complex tissues. We will develop algorithms and models for representing data the transcriptional profiles, DNA methylation landscapes and Hi-C maps of literally millions of cells. Our tools will be designed specifically to leverage on new single cell RNA-seq, single cell Hi-C, single cell capture-pBat and higher order 4C-seq that we will continue to develop experimentally. Furthermore, we shall enhance and optimize our interdisciplinary framework hand in hand with a working model aiming at unprecedentedly comprehensive single cell analysis of E8-E10 mouse embryos. This will provide us with hundreds of worked-out cases of tissue specific gene regulation. The techniques and insights from these studies will then be used to characterize cell type aberrations and epigenetic reprogramming in tumors. The open algorithms, techniques and methodology we shall develop can accelerate research in multiple groups that will utilize single cell genomics to study numerous questions on gene regulation in the coming years.

2 437 500 €

Start date: 2017-12-01, End date: 2022-11-30