General Biology Seminar

Our understanding of how the central dogma, that DNA makes RNA makes Protein, can illuminate us on the development of multicellular organisms, requires knowledge not only of the genome, but also of its 3D organization and its accompanying RNA and protein partners, that help to create different "epigenomes". Thanks to the advent of high throughput sequencing technologies, these different layers of information are now becoming accessible and enabling us to understand how differential expression of genes can be achieved in different cell types, during development and throughout the lifetime of an organism. Using the mammalian process of X-chromosome inactivation as a model, we are interested in understanding how the differential treatment of identical DNA sequences in the same nucleus can be achieved during early mammalian development. The establishment of X inactivation involves a complex locus, the Xic, which produces the non-coding Xist RNA that is the trigger for chromosome-wide silencing. X inactivation is also accompanied by numerous epigenetic modifications that ensure stability and heritability of the inactive state. By investigating the regulatory landscape of the Xic locus using chromosome-conformation capture technologies and super-resolution microscopy, we recently uncovered a new level of chromosome folding into topologically associating chromosome domains (TADs), each spanning hundreds of kilobases (Nora et al, 2012). TAD organization was shown to be highly conserved, genome-wide phenomenon in mammals (Dixon et al, 2012). Sequences within TADs tend to interact more frequently and may thus provide a scaffold for privileged interactions between genes and their regulatory sequences.  We demonstrated that within the Xic, TADs enable the precise coordination of gene expression dynamics during early differentiation and also underlie the partitioning of epigenomic landscapes, such as histone modifications. More recently, we further explored the functional relevance of TADs using physical modeling, as well as genetic engineering approaches at the Xic locus (Giorgetti et al, 2014). I will present our most recent work, investigating the mechanisms of X-inactivation initiation and exploring the relationships between chromosome dynamics and gene regulation.