ERC FUNDED PROJECTS

MAL: an actin-regulated SRF transcriptional coactivator Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology: ¿ Actin as a transcriptional regulator ¿ Actin as a signalling molecule ¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.

1 889 995 €

Start date: 2011-10-01, End date: 2017-09-30

The project aims at a breakthrough in our understanding of stellar evolution, by combining advanced observations of stellar oscillations with state-of-the-art modelling of stars. This will largely be based on very extensive and precise data on stellar oscillations from the NASA Kepler mission launched in March 2009, but additional high-quality data will also be included. In particular, my group is developing the global SONG network for observations of stellar oscillations. These observational efforts will be supplemented by sophisticated modelling of stellar evolution, and by the development of asteroseismic tools to use the observations to probe stellar interiors. This will lead to a far more reliable determination of stellar ages, and hence ages of other astrophysical objects; it will compare the properties of the Sun with other stars and hence provide an understanding of the life history of the Sun; it will investigate the physical processes that control stellar properties, both at the level of the thermodynamical properties of stellar plasmas and the hydrodynamical instabilities that play a central role in stellar evolution; and it will characterize central stars in extra-solar planetary systems, determining the size and age of the star and hence constrain the evolution of the planetary systems. The Kepler data will be analysed in a large international collaboration coordinated by our group. The SONG network, which will become partially operational during the present project, will yield even detailed information about the conditions in the interior of stars, allowing tests of subtle but central aspects of the physics of stellar interiors. The projects involve the organization of a central data archive for asteroseismic data, at the Royal Library, Copenhagen.

2 498 149 €

Start date: 2011-04-01, End date: 2016-03-31

The human genome is highly transcribed, with over 90% of sequences contributing to the production of RNA. The function of the vast majority of these RNAs is unknown. Evidence over many years has revealed that transcription factors and chromatin regulators are associated with a variety of non-coding (nc)RNAs, but their function remains largely unknown. There are a few cases where a role has been ascribed for ncRNAs in transcription, but no clear mechanistic insight has been defined yet. We predict that many of the newly identified ncRNAs emanating from the genome will play a role in transcriptional processes. We intend to identify and characterise such ncRNAs. This will take place in two phases. In the first phase we will use biochemical approaches to identify ncRNAs involved in the regulation of chromatin and transcription. Our investigations will focus on proteins leading to the induction of pluripotency and oncogenesis. ncRNAs associated with such proteins will be identified using targeted screens. In the second phase, the importance of these RNAs in determining pluripotency and oncogenesis will be analysed. In addition, a variety of molecular approaches will be used to investigate the mechanism by which these ncRNAs regulate the function of the proteins or complexes they associate with. One particular hypothesis we will explore is that such ncRNAs play a role in guiding proteins to DNA sequences, via the formation of RNA/DNA triplexes. This concerted and focused analysis will provide mechanistic insights into the functions of ncRNAs in transcriptional regulation and validate their role in key biological processes. The identification of such new ncRNA-regulated pathways may open up new avenues for therapeutic intervention.

2 141 470 €

Start date: 2011-05-01, End date: 2017-04-30

The goal of this research initiative is to construct large-scale computational modeling of how knowledge of the world emerges from the combination of innate mechanisms and visual experience. The ultimate goal is a ‘digital baby’ model which, through perception and interaction with the world, develops on its own representations of complex concepts that allow it to understand the world around it, in terms of objects, object categories, events, agents, actions, goals, social interactions, etc. A wealth of empirical research in the cognitive sciences have studied how natural concepts in these domains are acquired spontaneously and efficiently from perceptual experience, but a major open challenge is an understating of the processes and computations involved by rigorous testable models. To deal with this challenge we propose a novel methodology based on two components. The first, ‘computational Nativism’, is a computational theory of cognitively and biologically plausible innate structures , which guide the system along specific paths through its acquisition of knowledge, to continuously acquire meaningful concepts, which can be significant to the observer, but statistically inconspicuous in the sensory input. The second, ‘embedded interpretation’ is a new way of acquiring extended learning and interpretation processes. This is obtained by placing perceptual inference mechanisms within a broader perception-action loop, where the actions in the loop are not overt actions, but internal operation over internal representation. The results will provide new modeling and understanding of the age-old problem of how innate mechanisms and perception are combined in human cognition, and may lay foundation for a major research direction dealing with computational cognitive development.

1 647 175 €

Start date: 2011-06-01, End date: 2016-05-31