Description:

The Simpson Querrey Center for Epigenetics presents:

Francois Spitz, PhD
Professor, University of Chicago, Department of Human Genetics                       

Lecture Title: Molecular Determinants and Function of the Vertebrate 3D Genome Organization

Abstract: In vertebrates, the regulatory elements that control gene expression can lie several hundreds kilobases away from the promoter they influence. The biological role of these distant elements is particularly important during embryogenesis, as they often provide decisive instruction to key developmental regulators. Because of the distances involved, the activity of these elements is not only defined by their intrinsic regulatory potential, but also by their ability to transfer it to their target genes. Hence, their biological function is closely associated with the 3D-organization of the genome. 

Recent progresses have identified different levels of folding of chromosomes. In particular, the formation of the topologically-associating domains (TADs) has been proposed to play an important role in enabling the regulation of genes by distant enhancers. Yet, the underlying mechanisms are still poorly understood and highly debated. To understand how TADs influence enhancer-promoter interactions, we have systematically dissected few large genomic loci with in vivo chromosomal engineering techniques and interfered with TAD formation in different ways. 

Our data demonstrate that TADs essential to promote long-distance functional interactions. Importantly, these semi-isolated neighborhoods do not constitute domains of uniform gene regulation and the position of a gene within a TAD can significantly modulate its response to enhancer activity. I’ll discuss how our findings provide new insights to infer the regulatory and phenotypic consequences of the structural rearrangements and conformation changes observed in inherited genomic disorders or in cancers.