Spitz Group
Gene regulation and genome architecture in development and evolution
Previous and current research
While the major part of vertebrate genomes is not coding for proteins, it nevertheless contains functionally important information. In particular, the tightly regulated expression of many developmental genes is achieved through the coordinated action of multiple cis-regulatory elements, which could be located hundreds of kilobases away from the gene they control. Notably, many recent genome-wide association studies have identified disease susceptibility intervals that do not overlap with any protein-coding gene, suggesting that they instead contain elements influencing the expression of distant genes. These findings emphasise the critical role of non-genic sequences in controlling gene activities and the importance of defining precisely the location of such elements and their function. Importantly, the specific distribution of these elements along the chromosomes seems to play a major role in directing their activities, as shown by the dramatic consequences of chromosomal rearrangements and the frequent preservation of chromosomal syntenies during evolution.
Our lab aims to understand the mechanisms that define the regulatory structure of the mammalian genomes and control gene expression. Specifically, we aim to understand how the complex intermingled arrays of genes and cis-regulatory elements found in several loci are translated into gene-specific expression programs. To address this, our lab has developed several experimental approaches in the mouse that allow us to explore and assess the regulatory organisation of the mammalian genome both at a large scale and in great detail. In addition to mouse genetic and transgenic approaches, we have established a simple and efficient in vivo transposition system that enables us to characterise systematically the different kinds of regulatory activities present along a chromosome. In particular, we focus on intervals associated with developmental abnormalities, where we use chromosomal engineering techniques to generate series of chromosomal rearrangements that reproduce those found in human patients. Besides supplying mouse models to study the molecular etiology of these genomic disorders, these approaches provide insights into the regulatory architecture of these loci.
Future projects and goals
Chromatin, chromosomal conformation and gene expression: In the nucleus, chromosomes adopt diff erent spatial organisations depending on their transcriptional activities. Distant genomic regions could be brought in close physical proximity by the formation of large chromosomal loops, to favour functional interactions between remote enhancers and their target genes. However, the genomic elements and protein complexes that determine the formation of such specific long-range chromatin interactions are still poorly understood. By combining our advanced genomic engineering approaches with chromatin prof ling and conformation analyses (using next generation sequencing and imaging), we aim to understand how specific chromatin structures and conformations are established at defined loci and determine their functional significance in the context of a developing embryo.
Genome regulatory architecture, structural variations and evolution: The tools we have established greatly facilitate the functional exploration of the non-coding part of the genome. We are interested in further expanding these approaches, notably to understand the phenotypic consequences of structural variations or chromosomal aneuploidies found in humans. We are also interested in comparing the regulatory architecture of developmental gene loci between different species, to trace back its emergence and establish how it could have contributed to evolution of body forms.