ERC FUNDED PROJECTS

A great challenge in developmental biology research has been to understand how cell type specific expression programs are orchestrated through regulated access to chromatin. The interaction between non-coding RNAs and chromatin regulators is emerging as an exciting new research area with the potential to explain how chromatin modifications are targeted. Polycomb repressive complex 2 (PRC2) modifies chromatin to maintain developmental regulator genes specific for other cell types in a repressed state and is essential for embryogenesis across Metazoa. We have recently determined that CpG islands targeted by PRC2 generate a class of short non-coding RNAs. The RNAs are produced independently from mRNA, indicative of hitherto uncharacterised transcriptional processes. Furthermore, we have found that the PRC2 subunit Suz12 is an RNA binding protein and directly interacts with these short RNAs and with other RNAs in cells. The role of ncRNA in targeting PRC2 to CpG islands and the importance of PRC2 RNA binding activity for development remains to be understood. Our aims are to: 1. Determine the functional properties of CpG-island RNAs by A. identifying their conserved features, B. determining their role in polycomb targeting of CpG islands and C. investigating whether such a role relates to the antagonism of polycomb targeting by DNA methylation. 2. Establish the biological role for Suz12 RNA binding activity by A. determining the structural determinants for Suz12 binding in vitro, B. verifying these features play a role in PRC2 RNA binding in cells and C. determining the role for PRC2-RNA interactions for polycomb function and development. This work promises to characterise a potentially fundamental aspect of cell biology and will open a number of avenues for understanding the function of ncRNAs, the RNA binding activity of chromatin regulators, how transcription and chromatin structure are regulated, and how cell state is maintained and reshaped during development.

1 499 094 €

Start date: 2013-09-01, End date: 2019-04-30

Paget’s disease of bone (PDB) is a common disease characterised by focal areas of increased bone turnover leading to symptoms of bone pain, deformity, osteoarthritis and other complications. Genetic factors play an important role in PDB and mutations in SQSTM1 gene are responsible for ~10% of PDB cases with high penetrance. We have recently identified seven additional susceptibility loci for PDB using genome-wide association studies (Albagha et al, 2011; Nat Genet). These recently identified loci have a combined effect that explained about 13% of familial risk suggesting that other genetic factors remain to be identified. The aims of this project are three fold: 1) to define the functional variants in the recently identified susceptibility loci using targeted DNA sequencing, 2) To identify novel genetic variants for disease susceptibility using exome sequencing in PDB patients without SQSTM1 mutations, 3) To investigate the role of epigenetic factors and their interaction with genetic factors in the pathogenesis of PDB. We will study genome-wide DNA methylation patterns in PDB patients and controls to identify differentially methylated sites associated with PDB. The contribution of epigenetic factors to the focal nature of PDB will be studied using an animal model of PDB to assess if epigenetic changes are specific to bone lesions and to determine if these changes contribute to disease development or occur as a consequence of the disease. Identification of genetic and epigenetic factors that predispose to PDB will increase our understanding of disease mechanisms and could also identify novel molecular pathways that could form targets for new therapeutic treatment not only for Paget’s disease, but also other diseases associated with increased bone turnover. These factors could be used as markers for disease susceptibility to assess people at risk of developing PDB later in life and target those with the highest risk for early treatment.

1 493 544 €

Start date: 2012-10-01, End date: 2018-03-31

Structural economic models are getting increasingly complex. This complicates their implementation. In particular, for many models, (i) identification of the relevant components from data is still unresolved; (ii) estimation and testing procedures tend to be somewhat ad hoc and with no theoretical underpinning; (iii) the implementation of model and estimators often require numerical approximations since model solutions are not available on closed form. The proposed research aims at addressing these three issues, (i)-(iii), by developing new methods and results for identification, estimation, testing and implementation of structural models. Particular emphasis is put on the use of nonparametric techniques. Many of the projects involve empirical applications where the proposed methods will be taken to data. The individual projects making up the proposal are: Identification and inference in discrete choice models; identification and inference in continuous choice models; Implementation and estimation of parametric structural models; Filtering and likelihood inference in dynamic latent variable models; Bandwidth selection in estimation and testing of non- and semiparametric models.

1 067 000 €

Start date: 2012-10-01, End date: 2017-09-30

In this project, I study how economic development is shaped by cross-country knowledge flows via trade, foreign direct investment (FDI), and other channels. Using novel micro data for several Central and Eastern European (CEE) countries, I measure the quantitative importance of three channels: technical knowledge embodied in imported machinery, technical and organizational knowledge embodied in expatriate managers, and disembodied knowledge transfers taking place within multinational firms. I then analyze what impact foreign knowledge has on the firms and the workers of the host economy, and what are its implications for aggregate productivity and income inequality. The project relies on several existing databases for Hungary and Romania, which will be complemented with newly purchased, collected and compiled data. The outcome of the project will be seven research studies and a collection of firm-level data sets covering CEE countries, including a large cross-country firm survey on the local supplier linkages of multinational companies. My proposed project improves upon the state of the art in four ways. First, as a comprehensive study using novel micro data, it uncovers new facts about the relative importance of the channels of knowledge flows. Second, it improves the identification of causal effects relative to existing studies by exploiting the detailed micro data. Third, it uses the micro estimates to quantify the aggregate impact of foreign knowledge on the economy. Fourth, it discusses how foreign knowledge affects different firms and workers differently, and, more specifically, how it may contribute to income inequality. More broadly, the research findings help evaluate the relative efficacy of trade, FDI, and immigration policies in promoting economic growth and can inform theories about the channels and barriers of productivity convergence.

1 313 776 €

Start date: 2012-12-01, End date: 2017-11-30