Spitz Group

Previous and current research

Embryonic development is controlled by a large number of genes, whose expression levels and specificities are tightly regulated at the transcriptional level. In vertebrates, this is achieved for each gene through batteries of cis-regulatory elements, which act in modular, synergetic and complementary manners. These regulatory elements are often spread over large chromosomal domains that contain multiple genes with distinct functions and expression profiles. Hence, the mechanisms that translate such intermingled arrays of genes and cis-regulatory elements into coherent gene-specific expression programmes are playing a central role in controlling gene activity. The dramatic consequences of several human chromosomal rearrangements illustrate the importance of such mechanisms and the impact of the genome regulatory architecture on gene expression and function. Many recent genome-wide association studies and the extensive structural variations found in humans also underscore the importance for human phenotypic diversity of the mechanisms that control the interplay between genes and regulatory elements, and which are so far mostly elusive.

Our lab explores the nature of the vertebrate regulatory genome and aims to identify the underlying molecularmechanisms. Asmodel systems, we focus on few megabase-large genomic loci whose organisation is extensively conserved within vertebrates, or where rearrangements have been associated with developmental genetic abnormalities.We are using mouse transgenesis to identify the regulatory elements that control the specific activities of the multiple genes present in these loci, and state-of-the-art chromosomal engineering techniques to to reshuffle their organisation in various ways, including modelling known human genetic disorders. By combining these approaches, we are starting to unravel the intricate regulatory organisation of these loci, as well as getting insights into the mechanisms that control and restrict the functional interactions between cis-regulatory elements and neighbouring genes. It is known that changes in chromatin structure, conformation and localisation within the nucleus are associated with different transcriptional activities, but the hierarchy of these events and how they are determined by the genomic sequences are both poorly understood. Our engineered mouse lines with altered chromosomal organisation allow us to investigate the relationships between genome sequence, chromatin structure and gene expression, for which we combine phenotypic and gene expression analysis with chromatin profiling and imaging.We are also interested in comparing the regulatory architecture of these regions in different species, to trace back its emergence during evolution and the associated evolutionary regulatory tinkering.

Future projects and goals

By combining mouse genetics with computational, biochemical and functional genomic approaches, we are aiming to:

• Examine the relationship between the genome sequence and its functional and structural conformation in the cell nucleus, as well as identify potential protein complexes involved in the associated mechanisms.
• Explore the functional and regulatory organisation of the mammalian genome using in vivo transposition and recombination approaches. In particular, we are interested in developing models of structural variations found in humans to unravel their phenotypic consequences.
• Identify the mechanisms associated with the emergence of novel cis-regulatory modules during evolution, using both computational and functional approaches.We are particularly interested by the role of ancestral mobile elements which appear to have been exapted into yet-to-be-determined functions (project funded by HFSP, in collaboration with Gill Bejerano, Stanford).