SPITZ LAB
(Epi)Genomics of Development, Disease and Evolution
We are interested in understanding how the information that implements the different gene regulatory programs that control embryonic development and organogenesis is encoded in the genome. Differential control of gene expression is an integral part of this process, and it is, to a large extent, encoded in the plethora of cis-regulatory elements (mostly enhancers) that regulate gene promoter activities. Remarkably, these regulatory elements can be located megabases away from the gene(s) they control. Correspondingly, the function and influence of an enhancer are defined not only by its intrinsic regulatory potential but also by its ability to transfer this regulatory information to surrounding genes. We and others have shown how the spatial folding of the genome into specific 3D domains, loops and other structures plays an important role in organizing functional interactions between distant genes and their enhancers. Correspondingly, changes in the genome that interfere with its normal 3D folding may have a profound impact on its activities, even if they do not directly disrupt any functional element.
We are therefore studying both the molecular mechanisms that organize the 3D architecture of the vertebrate genomes and regulate the specificity and efficiency of distant enhancer-promoter interactions and their consequences in terms of human pathologies and vertebrate evolution.
Genomic changes impacting enhancer-promoter communication are causes of several human genetic conditions, including developmental abnormalities and cancers. They may underlie the phenotypic impacts of the many structural variants identified in human genomes. Yet, as our understanding of the non-coding genome remains limited, many of these structural variants are labeled as “of unknown significance.” By identifying the sets of instructions that guide the folding of a genomic locus into the specific regulatory ensemble that regulates enhancer-promoter interactions and gene expression, we aim to better identify in sequenced genomes the non-coding variants that may impact gene expression and, therefore, help to determine the genomic etiology of undiagnosed disorders.
Such genomic changes are also widely present between animal genomes, raising the possibility that changes in genome architecture may have also contributed to animal evolution. In this context, we are particularly interested in the consequences of the extensive reshuffling of the vertebrate genomes after the two whole-genome duplications that occurred early in this lineage.
To address these questions, we develop experimental and computational strategies to map the functional genomic architecture of a locus at high resolution, to change it in various ways, and to identify how these changes impact the gene-regulatory networks that determine cell identity. Our go-to approaches include next-generation genomic and epigenomic engineering with epigenomic profiling with ATAC-seq, ChIP-seq, Hi-C/micro-C, single-cell transcriptomic, and chromatin accessibility, which we use in a variety of settings ranging from human tumors, iPSCs, mouse embryos, and lampreys.