Eukaryotic genomes must accommodate two diametrically opposite requirements: on the one hand, the compaction of ~2 m of genomic DNA into a sphere with a diameter of ~10 µm and, on the other hand, the accessibility of DNA to a wide variety of molecular machines involved in DNA replication, transcription, recombination and repair. Three-dimensional nuclear organization is therefore clearly critical for cellular functions. The nuclear architecture in a differentiated cell results from several factors such as the linear sequence of a gene; long distance interactions between coregulated genes; epigenetic modifications altering DNA (methylation) or histone tails (acetylation, methylation, etc); and interactions between the genome and nuclear envelope components or proteinaceous nuclear sub-compartments. However, the complex interplay between them is not yet elucidated.
The muscle fibre is an ideal model to probe how cellular function is linked to nuclear architecture.
Muscle differentiation is a well-characterized model of cellular differentiation with mononucleated myoblasts irreversibly withdrawing from the cell cycle and differentiating into myocytes that fuse to form multinucleated terminally differentiated myotubes in an ordered series of events.In vivo, each multinucleated fibre is contacted by the axon of a motor neuron initiating the formation of a highly specialized structure dedicated to muscle / nerve communication, called the neuromuscular junction (NMJ). Motor innervation leads to the restriction of expression of synapse-specific genes to a few nuclei located directly under the synapse. Thus, the resulting mature muscle fibre is unique in mammals as it is the only multinucleated cell in which different genetic programs are expressed in different nuclei of the same cell.Finally, many mutations in nuclear envelope components have been linked to several human muscular dystrophies, suggesting that nuclear organization is critical for muscle differentiation/function. However, little is known about how nuclear architecture and dynamics change during muscle differentiation and how nuclear architecture contributes to muscle function.
Our team aims to address how genome organization changes during muscle differentiation and how these changes affect genome function.