ERC FUNDED PROJECTS

Chromatin is the ensemble of genomic DNA and hundreds of structural and regulatory proteins. Together these proteins govern the gene expression program of a cell. While biochemical and genetic approaches have tought us much about interactions between individual chromatin proteins, we still lack a “big picture” of chromatin: how is the entire interaction network of chromatin proteins organized? My lab discovered that chromatin in Drosophila consists of a limited number of principal types that partition the genome into domains with distinct regulatory properties. Among these is BLACK chromatin, a novel repressive type of chromatin that covers nearly half of the fly genome. It is still largely unclear how these different chromatin types are formed, how they are targeted to specific genomic regions, and how they interact with each other. Here, I propose a combination of systematic approaches aimed to gain insight into the basic mechanisms that drive the partioning of the genome into distinct chromatin types. New genomics techniques, developed in my laboratory, will be used to construct an integrated view of the interplay of more than one hundred representative chromatin proteins with each other and with sequence elements in the genome. Specifically, we will: (1) Study the genome-wide dynamic repositioning of chromatin domains during development in relation to gene regulation; (2) Use a novel and versatile parallel genome-wide reporter assay to dissect the interplay among DNA sequences and chromatin types; (3) Combine computational modeling with a high-throughput genome-wide assay to uncover the network of interactions responsible for the formation of the principal chromatin types; (4) Dissect the molecular architecture of BLACK chromatin and its role in gene repression. The results will provide understanding of the basic principles that govern the structure and composition of chromatin, and reveal how the principal chromatin types together direct gene expression.

2 495 080 €

Start date: 2012-03-01, End date: 2017-02-28

Mental retardation, like most common neurodevelopmental and psychiatric diseases, shows a strong genetic component, but these underlying genetic causes remain largely unknown. For a long time it was hypothesized that these kind of common diseases are mainly caused by common inherited genetic variants with reduced penetrance. In contrast to this common variant-common disease hypothesis, I here hypothesize that a large proportion of this so-called “missing heritability” for conditions such as mental retardation, schizophrenia, and autism lies in de novo genetic variation that is rapidly eliminated from the population because individuals with such diseases have severely compromised fecundity. My previous work using microarrays has already demonstrated de novo genomic copy number variations in mental retardation and in schizophrenia. However, microarrays do not allow us to capture the most common form of de novo mutations, those occurring at the nucleotide level. Technological innovations now for the first time allow us to comprehensively study the entire genome of an individual for genomic variations at all levels. In this project I will explore the de novo mutation hypothesis in whole exome and whole genome sequence data from patients with mental retardation. I will optimize and apply whole genome sequencing strategies using patient-parent trios, both in rare mental retardation syndromes as well as common forms of mental retardation. Guidelines for pathogenicity will be established by computational studies aimed at unraveling genotype-phenotype correlations in these family-based genome sequence type datasets. This project will contribute significantly to resolving the genetic causes of reproductively lethal disorders such as mental retardation, provide critical knowledge on the frequency and consequences of de novo mutations in our genome and help to establish medical genome sequencing as a routine diagnostic approach.

1 499 154 €

Start date: 2012-02-01, End date: 2017-01-31

"Double strand breaks (DSBs) repair is essential for normal development. While the complete inability to repair DSBs leads to embryonic lethality and cell death, mutations that hamper this repair cause genetically inherited syndromes, with or without cancer predisposition. The phenotypes associated with these syndromes are extremely varied, and can include growth and mental retardation, ataxia, skeletal abnormalities, immunodeficiency, premature aging, etc. Moreover, DSBs play an extremely relevant role in the biology of cancer. Alterations in the DSBs repair pathways facilitate tumour progression and are selected early on during cancer development. On the other hand, DSBs are the molecular base of radiotherapies and chemotherapies. This double role of DSBs in both, the genesis and treatment of cancer makes the understanding of the mechanisms that control their repair of capital importance in cancer research. DSBs are repaired by two major mechanisms that compete for the same substrate. Both ends of the DSB can be simple re-joined with little or no processing, a mechanism known as non-homologous end-joining. On the other hand, DSBs can be processed and engaged in a more complex repair pathway called homologous recombination. This pathway uses the information present in a homologue sequence. The balance between these two pathways is exquisitely controlled and its alteration leads to the appearance of chromosomal abnormalities and contribute to the diseases aforementioned. However, and despite its importance, the network controlling the choice between both is poorly understood. Here, we propose a series of research lines designed to investigate how the choice between both DSBs repair pathways is made, its relevance for cellular and organismal survival and disease, and its potential as a therapeutic target for the treatment of cancer and some genetically inherited disorders."

1 416 866 €

Start date: 2012-01-01, End date: 2016-12-31

Recent genome-wide association studies have successfully identified rare and common variants that correlate with complex traits. However, they have provided us with little insight into the nature of the genetic, biological and evolutionary relationships underlying such complex phenotypes. There is thus a growing need for approaches that provide a mechanistic understanding of how genetic variants function to impact phenotypic variation and why they have been substrates of natural selection. One set of traits that displays considerable heterogeneity and that has undoubtedly been shaped by natural selection is the host response to microorganisms. By integrating cutting-edge knowledge and technology in the fields of genomics, population genetics, immunology and bioinformatics, our aim is to establish a thorough understanding of how variable the human immune response is in the natural setting and how this phenotypic variation is under genetic control. Specifically, we aim (i) to characterise the genetic architecture of two populations differing in their ethnic background; (ii) to define individual and population-level variation in immune responses, in the same individuals, by establishing an ex vivo cell-based model to study levels of transcript abundance of both mRNA and miRNA, before and after activation with various immune stimuli; (iii) to map expression quantitative trait loci associated with variation in immune responses; and (iv) to identify adaptive immunological phenotypes. This study will increase our understanding of how genotypes influence the heterogeneity of immune response phenotypes at the level of the human population, and reveal immunological mechanisms under genetic control that have been crucial for our past and present survival against infection. In doing so, we will provide the foundations to define perturbations in these responses that correlate with the occurrence of various infectious and non-infectious diseases as well as with vaccine success.

1 494 756 €

Start date: 2012-01-01, End date: 2017-08-31